[ { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/brxbr-2nk64", "eprint_status": "archive", "datestamp": "2024-03-06 23:52:08", "lastmod": "2024-03-06 23:52:08", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chakrabarty-Yogaditya", "name": { "family": "Chakrabarty", "given": "Yogaditya" }, "orcid": "0000-0002-3230-9251" }, { "id": "Yang-Zheng", "name": { "family": "Yang", "given": "Zheng" }, "orcid": "0000-0002-7656-617X" }, { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "The HRI branch of the integrated stress response selectively triggers mitophagy", "ispublished": "pub", "full_text_status": "public", "keywords": "Cell Biology; Molecular Biology", "note": "
© 2024 Elsevier.
\n\nWe are grateful to A. Merchan, J. Repogle, J. Weissman, K. Page, R. She, and R. Voorhees for encouragement and advice on CRISPRi screening; D. Perez, J. Tijerina, and R. Diamond (Caltech Flow Cytometry and Cell Sorting Facility) for support with flow cytometry and FACS experiments; and I. Antoshechkin (Millard and Muriel Jacobs Genetics and Genomics Laboratory, Caltech) for support with next-generation sequencing. We thank the following investigators for contribution of important reagents: L. Jae, S. Yamashita, K. Yamano, N. Matsuda, G. Varuzhanyan, R. Youle, A. Ting, M. Moore, D. Ron, and J. Lippincott-Schwartz. We thank members of the Chan lab for helpful discussions and comments on the manuscript. This work was funded by the National Institutes of Health grant R35 GM127147 (D.C.C.).
\n\nConceptualization, Y.C. and D.C.C.; methodology, Y.C., Z.Y., and H.C.; investigation, Y.C., Z.Y., and H.C.; funding acquisition, D.C.C.; supervision, D.C.C.; writing – original draft, Y.C. and D.C.C.; writing – review & editing, Y.C., D.C.C., Z.Y., and H.C.
\n\nThe authors declare no competing interests.
\n\n\nNo additional resources were generated by this study.
\n\n\nTo maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson’s disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.
\n\u00a9 2023 Elsevier.
\n\nThis work was supported by the NIH grant R35GM127147.
\n\nThe authors have no conflicts of interest to declare.
", "abstract": "Mitochondrial fusion enables cooperation between the mitochondrial population and is critical for mitochondrial function. Phosphatidic acid (PA) on the mitochondrial surface has a key role in mitochondrial fusion. A recent study by Su et al. shows that the nucleoside diphosphate (NDP) kinase NME3 recognizes PA and mediates its effects on mitochondrial dynamics.
", "date": "2023-10-17", "date_type": "published", "publication": "Trends in Cell Biology", "publisher": "Cell Press", "issn": "0962-8924", "official_url": "https://authors.library.caltech.edu/records/k6fv0-7vk26", "funders": { "items": [ { "grant_number": "R35GM127147" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.tcb.2023.10.006", "resource_type": "article", "pub_year": "2023", "author_list": "Yang, Zheng and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/gykbx-vgy25", "eprint_id": 120134, "eprint_status": "archive", "datestamp": "2023-08-20 09:01:54", "lastmod": "2023-12-13 16:46:33", "type": "monograph", "metadata_visibility": "show", "creators": { "items": [ { "id": "Fry-Michelle-Y", "name": { "family": "Fry", "given": "Michelle Y." }, "orcid": "0000-0002-3209-5492" }, { "id": "Navarro-Paula-P", "name": { "family": "Navarro", "given": "Paula P." }, "orcid": "0000-0002-9123-1132" }, { "id": "Qin-Xingping", "name": { "family": "Qin", "given": "Xingping" }, "orcid": "0000-0003-3263-0843" }, { "id": "Inde-Zintes", "name": { "family": "Inde", "given": "Zintes" }, "orcid": "0000-0001-5564-1698" }, { "id": "Ananda-Virly-Y", "name": { "family": "Ananda", "given": "Virly Y." }, "orcid": "0000-0001-5590-1170" }, { "id": "Makhlouta-Lugo-Camila-S", "name": { "family": "Makhlouta Lugo", "given": "Camila" }, "orcid": "0000-0003-4655-8096" }, { "id": "Hakim-Pusparanee", "name": { "family": "Hakim", "given": "Pusparanee" }, "orcid": "0000-0002-9018-8179" }, { "id": "Luce-Brdiget-E", "name": { "family": "Luce", "given": "Bridget E." }, "orcid": "0000-0002-0107-5181" }, { "id": "Ge-Yifan", "name": { "family": "Ge", "given": "Yifan" }, "orcid": "0000-0001-9135-9569" }, { "id": "McDonald-Julie-L", "name": { "family": "McDonald", "given": "Julie L." }, "orcid": "0000-0002-3715-9619" }, { "id": "Ali-Ilzat", "name": { "family": "Ali", "given": "Ilzat" }, "orcid": "0000-0003-2019-5645" }, { "id": "Ha-Leillani-L", "name": { "family": "Ha", "given": "Leillani L." }, "orcid": "0000-0003-4478-660X" }, { "id": "Kleinstiver-Benjamin-P", "name": { "family": "Kleinstiver", "given": "Benjamin P." }, "orcid": "0000-0002-5469-0655" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Sarosiek-Kristopher-A", "name": { "family": "Sarosiek", "given": "Kristopher A." }, "orcid": "0000-0002-4618-5085" }, { "id": "Chao-Luke-H", "name": { "family": "Chao", "given": "Luke H." }, "orcid": "0000-0002-4849-4148" } ] }, "title": "In situ architecture of Opa1-dependent mitochondrial cristae remodeling", "ispublished": "unpub", "full_text_status": "public", "note": "The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. \n\nWe are grateful to Phat Vinh Dip, and Edward Brignole at the MIT.nano cryo-EM facility and Kang Song and Chen Xu at the University of Massachusetts cryo-EM facility for providing access to the cryo-EM microscopes and for all their help, advice, and maintenance of cryo-EM equipment. Electron microscopy was performed in the Microscopy Core of the Center for Systems Biology/Program in Membrane Biology, which is partially supported by an Inflammatory Bowel Disease Grant DK043351 and a Boston Area Diabetes and Endocrinology Research Center (BADERC) Award DK057521. We thank Connor Tou for assistance cloning guide RNAs. \n\nP.P.N. was supported by the Swiss National Science Foundation (SNF) Early Postdoc.Mobility P2BSP3_188112 and Postdoc.Mobility P400PB_199252 fellowships. Z.I. was supported by NIA award F32AG077861. This work was supported by a Mass General Hospital ECOR Howard M. Goodman Fellowship (to B.P.K.); Charles H. Hood Foundation Child Health Research Awards to L.H.C. and K.A.S.; and Alex's Lemonade Stand Foundation for Childhood Cancers Research Award to K.A.S. This work was supported by funding from the National Institutes of Health (R35GM142553 to L.H.C., R01DK125263 and R37CA248565 to K.A.S. \n\nAuthor Contributions. P.P.N. established cryo-FIB/cryo-ET imaging and processing pipeline. P.P.N., M.Y.F., Y.G., and J.L.M. acquired cryo-ET data. P.P.N and M.Y.F processed cryo-ET data and performed data analysis and quantification. P.P.N and I.A. performed STA analyses. P.H., B.L., Y.G., J.L.M., L.L.H., and B.P.K designed and prepared cell lines. D.C.C. generously provided the l-Opa1* and s-Opa1* cells. P.H., Y.G. performed fluorescence imaging. P.P.N. trained and supported V. A. with 3D segmentation and visualization of cryo-electron tomograms. V.A. performed segmentation of tomograms, subcompartment volume analyses, and prepared movies. C.M.L, B.L and J.L.M performed analyses of TEM images. Z.I., X.Q., performed BH3 profiling. M.Y.F., P.P.N., V.A., P.H., B.L., L.H.C. wrote the manuscript. All authors edited the manuscript. \n\nCompeting Interest Statement. B.P.K is an inventor on patents and/or patent applications filed by Mass General Brigham that describe genome engineering technologies. B.P.K. is a consultant for EcoR1 capital, and is an advisor to Acrigen Biosciences, Life Edit Therapeutics, and Prime Medicine. The remaining authors declare that there are no competing financial interests.\n\nSubmitted - 2023.01.16.524176v3.full.pdf
", "abstract": "Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to the lack of native 3D views of cristae morphology. We performin situcryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with well-defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe elongated mitochondria with a notable stacking phenotype, as well as an absence of tubular cristae, when only l-Opa1 is present. In contrast, when mitochondria contain mainly s-Opa1, we observe irregular cristae packing, an increase in globular cristae, and decreased matrix condensation. Notably, we find the absence of l-Opa1 results in mitochondria with wider cristae junctions. BH3 profiling reveals that absence of l-Opa1 reduces cytochrome c release in response to pro-apoptotic stimuli and protects cells from apoptosis induced by anti-cancer agents. We discuss the implications Opa1-dependent cristae morphologies in cell death initiation.HighlightsIn situultrastructural characterization of mitochondrial cristae with different forms of Opa1.Mitochondria with predominantly l-Opa1 show cristae stacking, longer cristae compared to WT, but also a reduction of globular cristae and no tubular cristae.Mitochondria with mostly s-Opa1 showed irregular cristae packing with wider cristae junctions and more narrow cristae than WT.BH3 profiling show Opa1-knock-out cells have reduced apoptotic priming and reduced sensitivity to apoptosis-inducing agents, and the presence l-Opa1 restores a WT protective apoptotic response.", "date": "2023-03-22", "date_type": "published", "id_number": "CaltechAUTHORS:20230316-182139000.16", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230316-182139000.16", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "DK043351" }, { "agency": "NIH", "grant_number": "DK057521" }, { "agency": "Swiss National Science Foundation (SNSF)", "grant_number": "P2BSP3_188112" }, { "agency": "Swiss National Science Foundation (SNSF)", "grant_number": "P400PB_199252" }, { "agency": "NIH Postdoctoral Fellowship", "grant_number": "F32AG077861" }, { "agency": "Massachusetts General Hospital" }, { "agency": "Charles H. Hood Foundation" }, { "agency": "Alex's Lemonade Stand Foundation for Childhood Cancers" }, { "agency": "NIH", "grant_number": "R35GM142553" }, { "agency": "NIH", "grant_number": "R01DK125263" }, { "agency": "NIH", "grant_number": "R37CA248565" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1101/2023.01.16.524176", "primary_object": { "basename": "2023.01.16.524176v3.full.pdf", "url": "https://authors.library.caltech.edu/records/gykbx-vgy25/files/2023.01.16.524176v3.full.pdf" }, "resource_type": "monograph", "pub_year": "2023", "author_list": "Fry, Michelle Y.; Navarro, Paula P.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/dkerj-8j320", "eprint_id": 119085, "eprint_status": "archive", "datestamp": "2023-08-22 18:36:08", "lastmod": "2023-12-22 23:24:04", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Murata-Daisuke", "name": { "family": "Murata", "given": "Daisuke" }, "orcid": "0000-0003-3829-6620" }, { "id": "Grunseich-Christopher", "name": { "family": "Grunseich", "given": "Christopher" }, "orcid": "0000-0003-4994-2472" }, { "id": "Iijima-Miho", "name": { "family": "Iijima", "given": "Miho" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" }, { "id": "Corse-Andrea", "name": { "family": "Corse", "given": "Andrea" }, "orcid": "0000-0001-6861-0823" }, { "id": "Hoke-Ahmet", "name": { "family": "Hoke", "given": "Ahmet" }, "orcid": "0000-0003-1215-3373" }, { "id": "Schindler-Alice", "name": { "family": "Schindler", "given": "Alice" } }, { "id": "Sesaki-Hiromi", "name": { "family": "Sesaki", "given": "Hiromi" }, "orcid": "0000-0002-6877-3929" }, { "id": "Roda-Ricardo-H", "name": { "family": "Roda", "given": "Ricardo H." }, "orcid": "0000-0002-3255-7749" } ] }, "title": "A Heterozygous Mutation in MFF Associated with a Mild Mitochondrial Phenotype", "ispublished": "pub", "full_text_status": "public", "keywords": "Neurology (clinical); Neurology", "note": "This work was made possible, in part, through philanthropic support from Dr. Peter Buck and additional anonymous contributors. CG and AS were supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. We would like to thank the NIH Intramural Sequencing Center (NISC) for whole-exome sequencing and Elizabeth Hartnett, MSW, who contributed as the patient care coordinator for the NIH neurogenetics clinic. MI is supported through NIH grant GM131768. HS is supported through NIH grant GM144103 and also support from the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation. DC is supported through NIH R35 GM127147.", "abstract": "Background: The number of mutations in nuclear encoded genes causing mitochondrial disease is ever increasing. Identification of these mutations is particularly important in the diagnosis of neuromuscular disorders as their presentation may mimic other acquired disorders. We present a novel heterozygous variant in mitochondrial fission factor (MFF) which mimics myasthenia gravis. \n\nObjective: To determine if the MFF c.937G>A, p.E313K variant causes a mild mitochondrial phenotype. Methods: We used whole exome sequencing (WES) to identify a novel heterozygous variant in MFF in a patient with ptosis, fatigue and muscle weakness. Using patient derived fibroblasts, we performed assays to evaluate mitochondrial and peroxisome dynamics. \n\nResults: We show that fibroblasts derived from this patient are defective in mitochondrial fission, despite normal recruitment of Drp1 to the mitochondria. Conclusions: The MFF c.937G>A, p.E313K variant leads to a mild mitochondrial phenotype and is associated with defective mitochondrial fission in patient-derived fibroblasts.", "date": "2023-01", "date_type": "published", "publication": "Journal of Neuromuscular Diseases", "volume": "10", "number": "1", "publisher": "IOS Press", "pagerange": "107-118", "id_number": "CaltechAUTHORS:20230207-728273600.6", "issn": "2214-3599", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230207-728273600.6", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Dr. Peter Buck" }, { "agency": "NIH", "grant_number": "GM131768" }, { "agency": "NIH", "grant_number": "GM144103" }, { "agency": "Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation" }, { "agency": "NIH", "grant_number": "R35 GM127147" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.3233/jnd-221532", "resource_type": "article", "pub_year": "2023", "author_list": "Murata, Daisuke; Grunseich, Christopher; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/7y9fw-bb376", "eprint_id": 117114, "eprint_status": "archive", "datestamp": "2023-08-22 17:49:45", "lastmod": "2023-12-22 23:26:10", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Dai-Wenting", "name": { "family": "Dai", "given": "Wenting" } }, { "id": "Wang-Zhichao", "name": { "family": "Wang", "given": "Zhichao" } }, { "id": "Wang-Qiong-A", "name": { "family": "Wang", "given": "Qiong A." }, "orcid": "0000-0003-2224-4287" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Jiang-Lei", "name": { "family": "Jiang", "given": "Lei" }, "orcid": "0000-0002-8596-556X" } ] }, "title": "Metabolic reprogramming in the OPA1-deficient cells", "ispublished": "pub", "full_text_status": "public", "keywords": "Cell Biology; Cellular and Molecular Neuroscience; Pharmacology; Molecular Biology; Molecular Medicine", "note": "We thank the Light Microscopy Core at City of Hope Medical Center for technical assistance.\n\nThe work was supported by Caltech-City of Hope Biomedical Research Initiative awarded to Lei Jiang, David Chan, and Qiong A. Wang, grant NIH R35 GM127147 to David Chan, and P30CA033572 to City of Hope. Qiong A. Wang was also supported by National Institutes of Health grants R01AG063854, R01HD096152, R01DK128907, and the American Diabetes Association Junior Faculty Development Award 1-19-JDF-023.", "abstract": "OPA1, a dynamin-related GTPase mutated in autosomal dominant optic atrophy, is essential for the fusion of the inner mitochondrial membrane. Although OPA1 deficiency leads to impaired mitochondrial morphology, the role of OPA1 in central carbon metabolism remains unclear. Here, we aim to explore the functional role and metabolic mechanism of OPA1 in cell fitness beyond the control of mitochondrial fusion. We applied [U-\u00b9\u00b3C]glucose and [U-13C]glutamine isotope tracing techniques to OPA1-knockout (OPA1-KO) mouse embryonic fibroblasts (MEFs) compared to OPA1 wild-type (OPA1-WT) controls. Furthermore, the resulting tracing data were integrated by metabolic flux analysis to understand the underlying metabolic mechanism through which OPA1 deficiency reprograms cellular metabolism. OPA1-deficient MEFs were depleted of intracellular citrate, which was consistent with the decreased oxygen consumption rate in these cells with mitochondrial fission that is not balanced by mitochondrial fusion. Whereas oxidative glucose metabolism was impaired, OPA1-deficient cells activated glutamine-dependent reductive carboxylation and subsequently relied on this reductive metabolism to produce cytosolic citrate as a predominant acetyl-CoA source for de novo fatty acid synthesis. Prevention of cytosolic glutamine reductive carboxylation by GSK321, an inhibitor of isocitrate dehydrogenase 1 (IDH1), largely repressed lipid synthesis and blocked cell proliferation in OPA1-deficient MEFs. Our data support that, when glucose oxidation failed to support lipogenesis and proliferation in cells with unbalanced mitochondrial fission, OPA1 deficiency stimulated metabolic anaplerosis into glutamine-dependent reductive carboxylation in an IDH1-mediated manner.", "date": "2022-10", "date_type": "published", "publication": "Cellular and Molecular Life Sciences", "volume": "79", "number": "10", "publisher": "Springer", "pagerange": "Art. No. 517", "id_number": "CaltechAUTHORS:20220922-931611600.11", "issn": "1420-682X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220922-931611600.11", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Caltech-City of Hope Biomedical Initiative" }, { "agency": "NIH", "grant_number": "R35 GM127147" }, { "agency": "NIH", "grant_number": "P30CA033572" }, { "agency": "NIH", "grant_number": "R01AG063854" }, { "agency": "NIH", "grant_number": "R01HD096152" }, { "agency": "NIH", "grant_number": "R01DK128907" }, { "agency": "American Diabetes Association Research Foundation", "grant_number": "1-19-JDF-023" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1007/s00018-022-04542-5", "resource_type": "article", "pub_year": "2022", "author_list": "Dai, Wenting; Wang, Zhichao; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/zzzaa-14w05", "eprint_id": 114100, "eprint_status": "archive", "datestamp": "2023-08-22 14:40:30", "lastmod": "2023-12-22 23:08:31", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yang-Huan", "name": { "family": "Yang", "given": "Huan" }, "orcid": "0000-0001-6140-2650" }, { "id": "Sibilla-Caroline", "name": { "family": "Sibilla", "given": "Caroline" } }, { "id": "Liu-Raymond", "name": { "family": "Liu", "given": "Raymond" } }, { "id": "Yun-Jina", "name": { "family": "Yun", "given": "Jina" } }, { "id": "Hay-B-A", "name": { "family": "Hay", "given": "Bruce A." }, "orcid": "0000-0002-5486-0482" }, { "id": "Blackstone-Craig", "name": { "family": "Blackstone", "given": "Craig" }, "orcid": "0000-0003-1261-9655" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Harvey-Robert-J", "name": { "family": "Harvey", "given": "Robert J." }, "orcid": "0000-0001-5956-6664" }, { "id": "Guo-Ming", "name": { "family": "Guo", "given": "Ming" }, "orcid": "0000-0002-1889-4271" } ] }, "title": "Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria", "ispublished": "pub", "full_text_status": "public", "keywords": "Mitochondria; Neural ageing; Parkinson's disease; RNA transport; General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry", "note": "\u00a9 The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \n\nReceived 13 January 2021; Accepted 04 February 2022; Published 24 March 2022. \n\nWe thank H.J. Bellen, A. Whitworth, and R.J. Youle for reagents, A.M. van der Bliek for comments on the manuscript, Y. Sun and P. Zheng for technical advice, and F.A. Laski, L. Dreier, E. Videlock, the BRI/UCLA EM Core Facility and the BSCRC/MCDB Microscopy Core Facility at UCLA for equipment. This work was supported by the China Scholarship Council Fellowship and UCLA Dissertation Year Fellowship to H.Y., the Wellcome Trust-NIH Ph.D. Studentship (WT088328AIA) to C.S., C.B., and R.J.H., the Intramural Research Program of the NINDS to C.B., and the R01 from the National Institute on Aging, Glenn Foundation for Medical Research, Kenneth Glenn Family Foundation, the Louis B. Mayer Foundation, the B. Freeman and R. Spogoli Fund for Aging and Neurodegeneration, the UCLA Laurie and Steven Gordon Commitment to Cure Parkinson's Disease, the Renee and Meyer Luskin Family Fund to M.G. \n\nData availability: All data are available within the Article, Supplementary Information, or Source Data file. Source data for Fig. 3a, b, and Supplementary Table 1 have been provided as Supplementary Table 2. All other source data are provided in the Source Data file with this paper. The knockout cell lines and transgenic flies generated in this work are available from the corresponding author upon request. Source data are provided with this paper. \n\nContributions: H.Y. designed, performed, and analyzed experiments and wrote the paper. C.S., R.L., J.Y., C.B., and R.J.H. designed, performed, and analyzed experiments. B.A.H. designed and analyzed experiments and wrote the paper. D.C.C. designed and analyzed experiments. M.G. designed and supervised the experiments, analyzed the results, provided the funding, and wrote the paper. \n\nThe authors declare no competing interests. \n\nPeer review information: Nature Communications thanks Dorothy Lerit and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.\n\nPublished - s41467-022-29071-4.pdf
Supplemental Material - 41467_2022_29071_MOESM1_ESM.pdf
Supplemental Material - 41467_2022_29071_MOESM2_ESM.pdf
Supplemental Material - 41467_2022_29071_MOESM3_ESM.pdf
Supplemental Material - 41467_2022_29071_MOESM4_ESM.xlsx
", "abstract": "Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.", "date": "2022-03-24", "date_type": "published", "publication": "Nature Communications", "volume": "13", "number": "1", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 1582", "id_number": "CaltechAUTHORS:20220328-640822600", "issn": "2041-1723", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220328-640822600", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "China Scholarship Council" }, { "agency": "UCLA" }, { "agency": "Wellcome Trust", "grant_number": "WT088328AIA" }, { "agency": "NIH" }, { "agency": "Glenn Foundation for Medical Research" }, { "agency": "Kenneth Glenn Family Foundation" }, { "agency": "Louis B. Mayer Foundation" }, { "agency": "B. Freeman and R. Spogoli Fund for Aging and Neurodegeneration" }, { "agency": "Renee and Meyer Luskin Family Fund" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41467-022-29071-4", "primary_object": { "basename": "41467_2022_29071_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/zzzaa-14w05/files/41467_2022_29071_MOESM1_ESM.pdf" }, "related_objects": [ { "basename": "41467_2022_29071_MOESM2_ESM.pdf", "url": "https://authors.library.caltech.edu/records/zzzaa-14w05/files/41467_2022_29071_MOESM2_ESM.pdf" }, { "basename": "41467_2022_29071_MOESM3_ESM.pdf", "url": "https://authors.library.caltech.edu/records/zzzaa-14w05/files/41467_2022_29071_MOESM3_ESM.pdf" }, { "basename": "41467_2022_29071_MOESM4_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/zzzaa-14w05/files/41467_2022_29071_MOESM4_ESM.xlsx" }, { "basename": "s41467-022-29071-4.pdf", "url": "https://authors.library.caltech.edu/records/zzzaa-14w05/files/s41467-022-29071-4.pdf" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Yang, Huan; Sibilla, Caroline; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/w5b3k-hfn24", "eprint_id": 114024, "eprint_status": "archive", "datestamp": "2023-08-22 14:39:41", "lastmod": "2023-12-22 23:26:08", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wareham-Lauren-K", "name": { "family": "Wareham", "given": "Lauren K." } }, { "id": "Liddelow-Shane-A", "name": { "family": "Liddelow", "given": "Shane A." } }, { "id": "Temple-Sally", "name": { "family": "Temple", "given": "Sally" } }, { "id": "Benowitz-Larry-I", "name": { "family": "Benowitz", "given": "Larry I." } }, { "id": "Di-Polo-Adriana", "name": { "family": "Di Polo", "given": "Adriana" } }, { "id": "Wellington-Cheryl", "name": { "family": "Wellington", "given": "Cheryl" } }, { "id": "Goldberg-Jeffrey-L", "name": { "family": "Goldberg", "given": "Jeffrey L." } }, { "id": "He-Zhigang", "name": { "family": "He", "given": "Zhigang" } }, { "id": "Duan-Xin", "name": { "family": "Duan", "given": "Xin" } }, { "id": "Bu-Guojun", "name": { "family": "Bu", "given": "Guojun" } }, { "id": "Davis-Albert-A", "name": { "family": "Davis", "given": "Albert A." } }, { "id": "Shekhar-Katrthik", "name": { "family": "Shekhar", "given": "Karthik" } }, { "id": "La-Torre-Anna", "name": { "family": "La Torre", "given": "Anna" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Canto-Soler-M-Valeria", "name": { "family": "Canto-Soler", "given": "M. Valeria" } }, { "id": "Flanagan-John-G", "name": { "family": "Flanagan", "given": "John G." } }, { "id": "Subramanian-Preeti", "name": { "family": "Subramanian", "given": "Preeti" } }, { "id": "Rossi-Sharyn", "name": { "family": "Rossi", "given": "Sharyn" } }, { "id": "Brunner-Thomas", "name": { "family": "Brunner", "given": "Thomas" } }, { "id": "Bovenkamp-Diane-E", "name": { "family": "Bovenkamp", "given": "Diane E." } }, { "id": "Calkins-David-J", "name": { "family": "Calkins", "given": "David J." }, "orcid": "0000-0002-8475-9959" } ] }, "title": "Solving neurodegeneration: common mechanisms and strategies for new treatments", "ispublished": "pub", "full_text_status": "public", "keywords": "Neurodegeneration, Alzheimer's Disease, Glaucoma, Parkinson's Disease, Huntington's Disease, Genetics, Metabolic stress, Neuro-regeneration, Neuro-replacement, Neurovascular coupling, Biomarker, Cell-replacement, Detection, Glia, Imaging, Model Systems, Organoids; Cellular and Molecular Neuroscience; Neurology (clinical); Molecular Biology", "note": "\u00a9 The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. \n\nReceived 17 November 2021. Accepted 18 February 2022. Published 21 March 2022. \n\nThe authors would like to acknowledge additional participants of the \"Solving Neurodegeneration Catalyst Meeting\" held virtually over several sessions in April 2021, including Ted and Terrence Barr, Aaron Gitler, Yang Hu, Nicholas Marsh-Armstrong, Arnon Rosenthal, and Donna Wilcock. We thank them for sharing their innovative research and ideas during the event. We are indebted to the generosity and staff of the Melza M. and Frank Theodore Barr Foundation, Glaucoma Research Foundation, and the BrightFocus Foundation for their support of this meeting. Figures for this review were created with BioRender.com. \n\nFunding for the \"Solving Neurodegeneration Catalyst Meeting\" and associated sessions was provided by BrightFocus Foundation, Glaucoma Research Foundation, and the Melza M. and Frank Theodore Barr Foundation. \n\nAvailability of data and materials. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. \n\nContributions. All authors conceived the ideas and concepts written in this review. LKW wrote the main text. LKW and DJC organized the main body of the text. SAL, ST, LB, ADP, CW, JLG, ZH, XD, GB, AAD, KS, ALT, DCC, MVCS, JGF, PS, SR, TB and DEB all provided substantial edits and expertise. All authors read and approved the final manuscript. \n\nEthics approval and consent to participate: N/A. \n\nConsent for publication: N/A. \n\nThe authors declare that there are no competing interests.\n\nPublished - s13024-022-00524-0.pdf
", "abstract": "Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled \"Solving Neurodegeneration\". This \"think-tank\" style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world's leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.", "date": "2022-03-21", "date_type": "published", "publication": "Molecular Neurodegeneration", "volume": "17", "publisher": "BioMed Central", "pagerange": "Art. No. 23", "id_number": "CaltechAUTHORS:20220323-704323000", "issn": "1750-1326", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220323-704323000", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "BrightFocus Foundation" }, { "agency": "Glaucoma Research Foundation" }, { "agency": "Melza M. and Frank Theodore Barr Foundation" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1186/s13024-022-00524-0", "pmcid": "PMC8935795", "primary_object": { "basename": "s13024-022-00524-0.pdf", "url": "https://authors.library.caltech.edu/records/w5b3k-hfn24/files/s13024-022-00524-0.pdf" }, "resource_type": "article", "pub_year": "2022", "author_list": "Wareham, Lauren K.; Liddelow, Shane A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/eq40r-qs364", "eprint_id": 112059, "eprint_status": "archive", "datestamp": "2023-09-15 07:13:41", "lastmod": "2023-12-22 23:24:02", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Sonn-Seong-Keun", "name": { "family": "Sonn", "given": "Seong Keun" } }, { "id": "Seo-Seungwoon", "name": { "family": "Seo", "given": "Seungwoon" } }, { "id": "Yang-Jaemoon", "name": { "family": "Yang", "given": "Jaemoon" } }, { "id": "Oh-Ki-Sook", "name": { "family": "Oh", "given": "Ki Sook" } }, { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Rhee-Kyung-S", "name": { "family": "Rhee", "given": "Kunsoo" }, "orcid": "0000-0002-5051-876X" }, { "id": "Lee-Kyung-S", "name": { "family": "Lee", "given": "Kyung S." } }, { "id": "Yang-Young", "name": { "family": "Yang", "given": "Young" } }, { "id": "Oh-Goo-Taeg", "name": { "family": "Oh", "given": "Goo Taeg" }, "orcid": "0000-0002-1104-1698" } ] }, "title": "ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1", "ispublished": "pub", "full_text_status": "public", "keywords": "Clinical Biochemistry; Molecular Biology; Molecular Medicine; Biochemistry", "note": "\u00a9 The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \n\nReceived 20 May 2021. Revised 03 September 2021. Accepted 07 September 2021. Published 26 November 2021. \n\nThis work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (Nos. 2021M3E5E7023628, 2020R1A3B2079811 and 2018R1D1A1B07050561). \n\nContributions. Conceptualization: S.K.S., Y.Y., and G.T.O.; Methodology, formal analysis, and writing \u2013 original draft: S.K.S. and G.T.O.; Investigation: S.K.S., S.S., and J.Y.; Writing \u2013 review and editing: G.T.O., H.C., D.C.C., K.R., and K.S.L.; Funding acquisition and supervision: G.T.O. \n\nThe authors declare no competing interests.\n\nPublished - s12276-021-00701-z.pdf
Supplemental Material - 12276_2021_701_MOESM1_ESM.pdf
", "abstract": "C1q/TNF-related protein 1 (CTRP1) is a CTRP family member that has collagenous and globular C1q-like domains. The secreted form of CTRP1 is known to be associated with cardiovascular and metabolic diseases, but its cellular roles have not yet been elucidated. Here, we showed that cytosolic CTRP1 localizes to the endoplasmic reticulum (ER) membrane and that knockout or depletion of CTRP1 leads to mitochondrial fission defects, as demonstrated by mitochondrial elongation. Mitochondrial fission events are known to occur through an interaction between mitochondria and the ER, but we do not know whether the ER and/or its associated proteins participate directly in the entire mitochondrial fission event. Interestingly, we herein showed that ablation of CTRP1 suppresses the recruitment of DRP1 to mitochondria and provided evidence suggesting that the ER\u2013mitochondrion interaction is required for the proper regulation of mitochondrial morphology. We further report that CTRP1 inactivation-induced mitochondrial fission defects induce apoptotic resistance and neuronal degeneration, which are also associated with ablation of DRP1. These results demonstrate for the first time that cytosolic CTRP1 is an ER transmembrane protein that acts as a key regulator of mitochondrial fission, providing new insight into the etiology of metabolic and neurodegenerative disorders.", "date": "2021-11-26", "date_type": "published", "publication": "Experimental and Molecular Medicine", "volume": "53", "publisher": "Korean Society of Medical Biochemistry and Molecular Biology", "pagerange": "1769-1780", "id_number": "CaltechAUTHORS:20211129-367530900", "issn": "1226-3613", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20211129-367530900", "funders": { "items": [ { "agency": "National Research Foundation of Korea", "grant_number": "2021M3E5E7023628" }, { "agency": "National Research Foundation of Korea", "grant_number": "2020R1A3B2079811" }, { "agency": "National Research Foundation of Korea", "grant_number": "2018R1D1A1B07050561" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s12276-021-00701-z", "pmcid": "PMC8639813", "primary_object": { "basename": "12276_2021_701_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/eq40r-qs364/files/12276_2021_701_MOESM1_ESM.pdf" }, "related_objects": [ { "basename": "s12276-021-00701-z.pdf", "url": "https://authors.library.caltech.edu/records/eq40r-qs364/files/s12276-021-00701-z.pdf" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Sonn, Seong Keun; Seo, Seungwoon; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/8p4xe-nq980", "eprint_id": 110672, "eprint_status": "archive", "datestamp": "2023-08-20 04:29:56", "lastmod": "2023-12-22 23:33:57", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Varuzhanyan-Grigor", "name": { "family": "Varuzhanyan", "given": "Grigor" }, "orcid": "0000-0001-6165-0857" }, { "id": "Ladinsky-Mark-S", "name": { "family": "Ladinsky", "given": "Mark S." }, "orcid": "0000-0002-1036-3513" }, { "id": "Yamashita-Shun-ichi", "name": { "family": "Yamashita", "given": "Shun-ichi" } }, { "id": "Abe-Manabu", "name": { "family": "Abe", "given": "Manabu" } }, { "id": "Sakimura-Kenji", "name": { "family": "Sakimura", "given": "Kenji" } }, { "id": "Kanki-Tomotake", "name": { "family": "Kanki", "given": "Tomotake" }, "orcid": "0000-0001-9646-5379" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation", "ispublished": "pub", "full_text_status": "public", "keywords": "Autophagy, Mitochondrial dynamics, Mitophagy, Spermatid, Spermatogenesis, Mouse", "note": "\u00a9 2021. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. \n\nReceived: 06 Apr 2021; Accepted: 13 Jul 2021. \n\nWe are grateful to Hsiuchen Chen for help with generating conditional Fis1 mice, for work on the early part of this project, and for overall guidance. We thank the rest of the Chan lab members for helpful discussions. We thank the Caltech Kavli Nanoscience Institute for maintenance of the TF-30 electron microscope. \n\nThis work was supported by the National Institutes of Health [R35 GM127147 to D.C.C.]; a National Science Foundation Graduate Research Fellowship [DGE-1144469 to G.V.]; a National Institutes of Health Cell and Molecular Biology Training Grant [GM07616T32 to G.V.]; a Japan Society for the Promotion of Science (JSPS) KAKENHI grant [16KK0162 to S.Y.]; a JSPS KAKENHI grant [16H06276 to T.K.]; M.S.L. was supported by the National Institute of Allergy and Infectious Diseases (NIAID) (2 P50 AI150464) (awarded to Pamela J. Bjorkman, Caltech). Open access funding provided by California Institute of Technology. Deposited in PMC for immediate release. \n\nAuthor contributions: Conceptualization: D.C.C.; Investigation: G.V., M.S.L.; Resources: S.Y., M.A., K.S., T.K.; Writing - original draft: G.V.; Writing - review & editing: D.C.C.; Supervision: D.C.C.; Funding acquisition: D.C.C. \n\nThe authors declare no competing or financial interests.\n\nPublished - dev199686_pub.pdf
Supplemental Material - dev199686supp.pdf
", "abstract": "Male germline development involves choreographed changes to mitochondrial number, morphology and organization. Mitochondrial reorganization during spermatogenesis was recently shown to require mitochondrial fusion and fission. Mitophagy, the autophagic degradation of mitochondria, is another mechanism for controlling mitochondrial number and physiology, but its role during spermatogenesis is largely unknown. During post-meiotic spermatid development, restructuring of the mitochondrial network results in packing of mitochondria into a tight array in the sperm midpiece to fuel motility. Here, we show that disruption of mouse Fis1 in the male germline results in early spermatid arrest that is associated with increased mitochondrial content. Mutant spermatids coalesce into multinucleated giant cells that accumulate mitochondria of aberrant ultrastructure and numerous mitophagic and autophagic intermediates, suggesting a defect in mitophagy. We conclude that Fis1 regulates mitochondrial morphology and turnover to promote spermatid maturation.", "date": "2021-08", "date_type": "published", "publication": "Development", "volume": "148", "number": "16", "publisher": "Company of Biologists", "pagerange": "Art. No. dev199686", "id_number": "CaltechAUTHORS:20210831-213708833", "issn": "0950-1991", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210831-213708833", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R35 GM127147" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1144469" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "GM07616T32" }, { "agency": "Japan Society for the Promotion of Science (JSPS)", "grant_number": "16KK0162" }, { "agency": "Japan Society for the Promotion of Science (JSPS)", "grant_number": "16H06276" }, { "agency": "NIH", "grant_number": "2 P50 AI150464" }, { "agency": "Caltech" } ] }, "local_group": { "items": [ { "id": "Kavli-Nanoscience-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1242/dev.199686", "pmcid": "PMC8380467", "primary_object": { "basename": "dev199686_pub.pdf", "url": "https://authors.library.caltech.edu/records/8p4xe-nq980/files/dev199686_pub.pdf" }, "related_objects": [ { "basename": "dev199686supp.pdf", "url": "https://authors.library.caltech.edu/records/8p4xe-nq980/files/dev199686supp.pdf" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Varuzhanyan, Grigor; Ladinsky, Mark S.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/613zs-t5d59", "eprint_id": 107554, "eprint_status": "archive", "datestamp": "2023-08-22 09:41:23", "lastmod": "2023-12-22 23:33:55", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Varuzhanyan-Grigor", "name": { "family": "Varuzhanyan", "given": "Grigor" }, "orcid": "0000-0001-6165-0857" }, { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Rojansky-Rebecca", "name": { "family": "Rojansky", "given": "Rebecca" } }, { "id": "Ladinsky-Mark-S", "name": { "family": "Ladinsky", "given": "Mark S." }, "orcid": "0000-0002-1036-3513" }, { "id": "McCaffery-J-Michael", "name": { "family": "McCaffery", "given": "J. Michael" }, "orcid": "0000-0001-7153-9933" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial fission factor (Mff) is required for organization of the mitochondrial sheath in spermatids", "ispublished": "pub", "full_text_status": "public", "keywords": "Mitochondrial fission; Spermatogenesis; Mitochondrial sheath", "note": "\u00a9 2021 Elsevier. \n\nReceived 23 June 2020, Revised 4 January 2021, Accepted 6 January 2021, Available online 19 January 2021. \n\nWe thank all members of the Chan Lab for helpful discussions. We thank the Caltech Kavli Nanoscience Institute for maintenance of the TF-30 electron microscope. \n\nThis work was supported by the National Institutes of Health (R35 GM127147). Grigor Varuzhanyan was supported by a National Science Foundation Graduate Research Fellowship (DGE-1144469) and a National Institutes of Health Cell and Molecular Biology Training Grant (GM07616T32). Mark S. Ladinsky was supported by the National Institute of Allergy and Infectious Diseases (NIAID) (2 P50 AI150464) (awarded to Pamela J. Bjorkman, Caltech). \n\nCredit author statement: Grigor Varuzhanyan:. Hsiuchen Chen:. Rebecca Rojansky:. Mark S Ladinsky: Investigation. J. Michael McCaffery: Investigation. David C. Chan:. \n\nThe authors declare no competing interests.\n\nAccepted Version - nihms-1664330.pdf
Supplemental Material - 1-s2.0-S0304416521000040-mmc1_lrg.jpg
Supplemental Material - 1-s2.0-S0304416521000040-mmc2.mp4
Supplemental Material - 1-s2.0-S0304416521000040-mmc3.mp4
Supplemental Material - 1-s2.0-S0304416521000040-mmc4.mp4
Supplemental Material - 1-s2.0-S0304416521000040-mmc5.mp4
Supplemental Material - 1-s2.0-S0304416521000040-mmc6.mp4
Supplemental Material - 1-s2.0-S0304416521000040-mmc7.mp4
", "abstract": "Background: Mitochondrial fission counterbalances fusion to maintain organelle morphology, but its role during development remains poorly characterized. Mammalian spermatogenesis is a complex developmental process involving several drastic changes to mitochondrial shape and organization. Mitochondria are generally small and spherical in spermatogonia, elongate during meiosis, and fragment in haploid round spermatids. Near the end of spermatid maturation, small mitochondrial spheres line the axoneme, elongate, and tightly wrap around the midpiece to form the mitochondrial sheath, which is critical for fueling flagellar movements. It remains unclear how these changes in mitochondrial morphology are regulated and how they affect sperm development. \n\nMethods: We used genetic ablation of Mff (mitochondrial fission factor) in mice to investigate the role of mitochondrial fission during mammalian spermatogenesis. \n\nResults: Our analysis indicates that Mff is required for mitochondrial fragmentation in haploid round spermatids and for organizing mitochondria in the midpiece in elongating spermatids. In Mff mutant mice, round spermatids have aberrantly elongated mitochondria that often show central constrictions, suggestive of failed fission events. In elongating spermatids and spermatozoa, mitochondrial sheaths are disjointed, containing swollen mitochondria with large gaps between organelles. These mitochondrial abnormalities in Mff mutant sperm are associated with reduced respiratory chain Complex IV activity, aberrant sperm morphology and motility, and reduced fertility. \n\nConclusions: Mff is required for organization of the mitochondrial sheath in mouse sperm. \n\nGeneral Significance: Mitochondrial fission plays an important role in regulating mitochondrial organization during a complex developmental process.", "date": "2021-05", "date_type": "published", "publication": "Biochimica et Biophysica Acta - General Subjects", "volume": "1865", "number": "5", "publisher": "Elsevier", "pagerange": "Art. No. 129845", "id_number": "CaltechAUTHORS:20210119-143306934", "issn": "0304-4165", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210119-143306934", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R35 GM127147" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1144469" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "GM07616T32" }, { "agency": "NIH", "grant_number": "2 P50 AI150464" } ] }, "local_group": { "items": [ { "id": "Kavli-Nanoscience-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.bbagen.2021.129845", "pmcid": "PMC7904653", "primary_object": { "basename": "1-s2.0-S0304416521000040-mmc5.mp4", "url": "https://authors.library.caltech.edu/records/613zs-t5d59/files/1-s2.0-S0304416521000040-mmc5.mp4" }, "related_objects": [ { "basename": "1-s2.0-S0304416521000040-mmc6.mp4", "url": "https://authors.library.caltech.edu/records/613zs-t5d59/files/1-s2.0-S0304416521000040-mmc6.mp4" }, { "basename": "1-s2.0-S0304416521000040-mmc7.mp4", "url": "https://authors.library.caltech.edu/records/613zs-t5d59/files/1-s2.0-S0304416521000040-mmc7.mp4" }, { "basename": "nihms-1664330.pdf", "url": "https://authors.library.caltech.edu/records/613zs-t5d59/files/nihms-1664330.pdf" }, { "basename": "1-s2.0-S0304416521000040-mmc1_lrg.jpg", "url": "https://authors.library.caltech.edu/records/613zs-t5d59/files/1-s2.0-S0304416521000040-mmc1_lrg.jpg" }, { "basename": "1-s2.0-S0304416521000040-mmc2.mp4", "url": "https://authors.library.caltech.edu/records/613zs-t5d59/files/1-s2.0-S0304416521000040-mmc2.mp4" }, { "basename": "1-s2.0-S0304416521000040-mmc3.mp4", "url": "https://authors.library.caltech.edu/records/613zs-t5d59/files/1-s2.0-S0304416521000040-mmc3.mp4" }, { "basename": "1-s2.0-S0304416521000040-mmc4.mp4", "url": "https://authors.library.caltech.edu/records/613zs-t5d59/files/1-s2.0-S0304416521000040-mmc4.mp4" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Varuzhanyan, Grigor; Chen, Hsiuchen; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/6snv8-3rq78", "eprint_id": 106876, "eprint_status": "archive", "datestamp": "2023-08-20 01:25:04", "lastmod": "2023-12-22 23:13:25", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wang-Ruohan", "name": { "family": "Wang", "given": "Ruohan" }, "orcid": "0000-0001-8361-4005" }, { "id": "Mishra-Prashant", "name": { "family": "Mishra", "given": "Prashant" } }, { "id": "Garbis-Spiros-D", "name": { "family": "Garbis", "given": "Spiros D." }, "orcid": "0000-0002-1050-0805" }, { "id": "Moradian-Annie", "name": { "family": "Moradian", "given": "Annie" }, "orcid": "0000-0002-0407-2031" }, { "id": "Sweredoski-Michael-J", "name": { "family": "Sweredoski", "given": "Michael J." }, "orcid": "0000-0003-0878-3831" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Identification of new OPA1 cleavage site reveals that short isoforms regulate mitochondrial fusion", "ispublished": "pub", "full_text_status": "public", "keywords": "OPA1, mitochondrial dynamics, mitochondrial fusion, dynamin, GTP hydrolyzing enzyme, membrane fusion", "note": "\u00a9 2021 Wang et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution\u2013Noncommercial\u2013Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). \n\nReceived: Sep 22, 2020; Revised: Nov 9, 2020; Accepted: Nov 16, 2020. \n\nWe thank Thomas Langer (Max-Planck-Institute for Biology of Ageing) for the Oma1-null, Yme1l-null, and Oma1/Yme1l-null cells. We thank Carlos L\u00f3pez Otin (Universidad de Oviedo) for the Oma1 knockout mice. This work was supported by a grant to D.C.C. from the National Institute of General Medical Sciences (R35GM127147). \n\nThe authors declare they have no conflicts of interest with the contents of this article. \n\nAuthor contributions: R.W. and D.C.C. conceptualized the project, analyzed the data, and wrote the manuscript. R.W. carried out the experimental analysis. P.M. performed the PA-GFP fusion assays. A.M. performed the LC-MS experiments. The data were analyzed by S.D.G. and M.J.S.\n\nPublished - mbc.e20-09-0605.pdf
Supplemental Material - combinedsupmats.pdf
Supplemental Material - reviewhistory.pdf
", "abstract": "OPA1, a large GTPase of the dynamin superfamily, mediates fusion of the mitochondrial inner membranes, regulates cristae morphology, and maintains respiratory chain function. Inner membrane\u2013anchored long forms of OPA1 (l-OPA1) are proteolytically processed by the OMA1 or YME1L proteases, acting at cleavage sites S1 and S2, respectively, to produce short forms (s-OPA1). In both mice and humans, half of the mRNA splice forms of Opa1 are constitutively processed to yield exclusively s-OPA1. However, the function of s-OPA1 in mitochondrial fusion has been debated, because in some stress conditions, s-OPA1 is dispensable for fusion. By constructing cells in which the Opa1 locus no longer produces transcripts with S2 cleavage sites, we generated a simplified system to identify the new YME1L-dependent site S3 that mediates constitutive and complete cleavage of OPA1. We show that mitochondrial morphology is highly sensitive to the ratio of l-OPA1 to s-OPA1, indicating that s-OPA1 regulates mitochondrial fusion.", "date": "2021-01-15", "date_type": "published", "publication": "Molecular Biology of the Cell", "volume": "32", "number": "2", "publisher": "American Society for Cell Biology", "pagerange": "157-168", "id_number": "CaltechAUTHORS:20201202-104543824", "issn": "1059-1524", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201202-104543824", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R35GM127147" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1091/mbc.e20-09-0605", "pmcid": "PMC8120690", "primary_object": { "basename": "combinedsupmats.pdf", "url": "https://authors.library.caltech.edu/records/6snv8-3rq78/files/combinedsupmats.pdf" }, "related_objects": [ { "basename": "mbc.e20-09-0605.pdf", "url": "https://authors.library.caltech.edu/records/6snv8-3rq78/files/mbc.e20-09-0605.pdf" }, { "basename": "reviewhistory.pdf", "url": "https://authors.library.caltech.edu/records/6snv8-3rq78/files/reviewhistory.pdf" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Wang, Ruohan; Mishra, Prashant; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/35ymr-0wv86", "eprint_id": 107394, "eprint_status": "archive", "datestamp": "2023-08-22 08:26:58", "lastmod": "2023-12-22 23:13:23", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Shin-Chun-Shik", "name": { "family": "Shin", "given": "Chun-Shik" }, "orcid": "0000-0002-1382-9876" }, { "id": "Meng-Shuxia", "name": { "family": "Meng", "given": "Shuxia" } }, { "id": "Garbis-Spiros-D", "name": { "family": "Garbis", "given": "Spiros D." }, "orcid": "0000-0002-1050-0805" }, { "id": "Moradian-Annie", "name": { "family": "Moradian", "given": "Annie" }, "orcid": "0000-0002-0407-2031" }, { "id": "Taylor-Robert-W", "name": { "family": "Taylor", "given": "Robert W." }, "orcid": "0000-0002-7768-8873" }, { "id": "Sweredoski-M-J", "name": { "family": "Sweredoski", "given": "Michael J." }, "orcid": "0000-0003-0878-3831" }, { "id": "Lomenick-Brett", "name": { "family": "Lomenick", "given": "Brett" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "LONP1 and mtHSP70 cooperate to promote mitochondrial protein folding", "ispublished": "pub", "full_text_status": "public", "keywords": "Chaperones; Mitochondria; Protein translocation", "note": "\u00a9 The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \n\nReceived 02 April 2020; Accepted 10 December 2020; Published 11 January 2021. \n\nData availability: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD021939. Source data are provided with this paper. \n\nThe authors declare no competing interests. \n\nPeer review information: Nature Communications thanks Cheryl F. Lichti, Carolyn Suzuki, and other, anonymous, reviewers for their contributions to hte peer review of this work. Peer review reports are available.\n\nPublished - s41467-020-20597-z.pdf
Supplemental Material - 41467_2020_20597_MOESM1_ESM.pdf
Supplemental Material - 41467_2020_20597_MOESM2_ESM.pdf
Supplemental Material - 41467_2020_20597_MOESM3_ESM.xlsx
Supplemental Material - 41467_2020_20597_MOESM4_ESM.xlsx
Supplemental Material - 41467_2020_20597_MOESM5_ESM.xlsx
Supplemental Material - 41467_2020_20597_MOESM6_ESM.xlsx
Supplemental Material - 41467_2020_20597_MOESM7_ESM.docx
Supplemental Material - 41467_2020_20597_MOESM8_ESM.pdf
Supplemental Material - 41467_2020_20597_MOESM9_ESM.xlsx
", "abstract": "Most mitochondrial precursor polypeptides are imported from the cytosol into the mitochondrion, where they must efficiently undergo folding. Mitochondrial precursors are imported as unfolded polypeptides. For proteins of the mitochondrial matrix and inner membrane, two separate chaperone systems, HSP60 and mitochondrial HSP70 (mtHSP70), facilitate protein folding. We show that LONP1, an AAA+ protease of the mitochondrial matrix, works with the mtHSP70 chaperone system to promote mitochondrial protein folding. Inhibition of LONP1 results in aggregation of a protein subset similar to that caused by knockdown of DNAJA3, a co-chaperone of mtHSP70. LONP1 is required for DNAJA3 and mtHSP70 solubility, and its ATPase, but not its protease activity, is required for this function. In vitro, LONP1 shows an intrinsic chaperone-like activity and collaborates with mtHSP70 to stabilize a folding intermediate of OXA1L. Our results identify LONP1 as a critical factor in the mtHSP70 folding pathway and demonstrate its proposed chaperone activity.", "date": "2021-01-11", "date_type": "published", "publication": "Nature Communications", "volume": "12", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 265", "id_number": "CaltechAUTHORS:20210111-122716111", "issn": "2041-1723", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210111-122716111", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R35 GM127147" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41467-020-20597-z", "pmcid": "PMC7801493", "primary_object": { "basename": "41467_2020_20597_MOESM7_ESM.docx", "url": "https://authors.library.caltech.edu/records/35ymr-0wv86/files/41467_2020_20597_MOESM7_ESM.docx" }, "related_objects": [ { "basename": "s41467-020-20597-z.pdf", "url": "https://authors.library.caltech.edu/records/35ymr-0wv86/files/s41467-020-20597-z.pdf" }, { "basename": "41467_2020_20597_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/35ymr-0wv86/files/41467_2020_20597_MOESM1_ESM.pdf" }, { "basename": "41467_2020_20597_MOESM2_ESM.pdf", "url": "https://authors.library.caltech.edu/records/35ymr-0wv86/files/41467_2020_20597_MOESM2_ESM.pdf" }, { "basename": "41467_2020_20597_MOESM3_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/35ymr-0wv86/files/41467_2020_20597_MOESM3_ESM.xlsx" }, { "basename": "41467_2020_20597_MOESM6_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/35ymr-0wv86/files/41467_2020_20597_MOESM6_ESM.xlsx" }, { "basename": "41467_2020_20597_MOESM4_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/35ymr-0wv86/files/41467_2020_20597_MOESM4_ESM.xlsx" }, { "basename": "41467_2020_20597_MOESM5_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/35ymr-0wv86/files/41467_2020_20597_MOESM5_ESM.xlsx" }, { "basename": "41467_2020_20597_MOESM8_ESM.pdf", "url": "https://authors.library.caltech.edu/records/35ymr-0wv86/files/41467_2020_20597_MOESM8_ESM.pdf" }, { "basename": "41467_2020_20597_MOESM9_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/35ymr-0wv86/files/41467_2020_20597_MOESM9_ESM.xlsx" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Shin, Chun-Shik; Meng, Shuxia; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/t7h7v-1wr36", "eprint_id": 107356, "eprint_status": "archive", "datestamp": "2023-08-22 08:24:23", "lastmod": "2023-12-22 23:24:00", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kato-Mitsuo", "name": { "family": "Kato", "given": "Mitsuo" }, "orcid": "0000-0002-1783-1084" }, { "id": "Abdollahi-Maryam", "name": { "family": "Abdollahi", "given": "Maryam" }, "orcid": "0000-0002-1989-6068" }, { "id": "Tunduguru-Ragadeepthi", "name": { "family": "Tunduguru", "given": "Ragadeepthi" }, "orcid": "0000-0001-7075-5511" }, { "id": "Tsark-Walter", "name": { "family": "Tsark", "given": "Walter" } }, { "id": "Chen-Zhuo", "name": { "family": "Chen", "given": "Zhuo" }, "orcid": "0000-0002-3522-9660" }, { "id": "Wu-Xiwei", "name": { "family": "Wu", "given": "Xiwei" }, "orcid": "0000-0002-7071-1671" }, { "id": "Wang-Jinhui", "name": { "family": "Wang", "given": "Jinhui" } }, { "id": "Chen-Zhen-Bouman", "name": { "family": "Chen", "given": "Zhen Bouman" }, "orcid": "0000-0002-3291-1090" }, { "id": "Lin-Feng-Mao", "name": { "family": "Lin", "given": "Feng-Mao" }, "orcid": "0000-0003-4042-0096" }, { "id": "Lanting-Linda", "name": { "family": "Lanting", "given": "Linda" } }, { "id": "Wang-Mei", "name": { "family": "Wang", "given": "Mei" } }, { "id": "Huss-Janice", "name": { "family": "Huss", "given": "Janice" } }, { "id": "Fueger-Patrick-T", "name": { "family": "Fueger", "given": "Patrick T." }, "orcid": "0000-0003-0602-6458" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" }, { "id": "Natarajan-Rama", "name": { "family": "Natarajan", "given": "Rama" }, "orcid": "0000-0003-4494-1788" } ] }, "title": "miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1", "ispublished": "pub", "full_text_status": "public", "keywords": "End-stage renal disease; Genetic engineering", "note": "\u00a9 The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \n\nReceived 27 May 2020; Accepted 23 November 2020; Published 04 January 2021. \n\nThese studies were supported by grants from the National Institutes of Health (NIH), R01 DK081705, R01 DK058191, and R01 HL106089 (to R.N.), the Wanek Family Project for the Cure of Type 1 diabetes at City of Hope (to R.N. and M.K.), R01HL145170 (to Z.B.C.), the American Diabetes Association ADA-1-18-IBS-103 (to J.H.) and a Postdoctoral fellowship from the Larry L. Hillblom Foundation (to R.T.). We are grateful to members of the Natarajan laboratory for helpful discussions. Research reported in this publication included work performed in the following Cores: Pathology Research Services, Integrative Genomics and Bioinformatics, and Comprehensive Metabolic Phenotyping, supported by the National Cancer Institute of the NIH under award number P30CA33572, as well as the Animal Resource Center, Transgenic/Knockout Animal and Electron Microscopy (EM/AFM) Cores at City of Hope. We are grateful to Dr. Zhuo Li and Ricardo Zerda Noriega of the EM/AFM Core at City of Hope for their help with preparation of samples for TEM and the imaging. \n\nData availability: All sequencing datasets generated in this study have been deposited into GEO with GEO #s GSE142596, GSE142597, and GSE142598. The source data underlying the graphs in figures are provided in Supplementary Data 1 and 2. Full gel is shown in Supplementary Information. All relevant data are available from the authors upon request. \n\nThese authors contributed equally: Mitsuo Kato, Maryam Abdollahi. \n\nAuthor Contributions: M.K., M.A., and R.N. designed research. M.K., M.A., M.W., R.T., and L.L. performed research. M.K., M.A., Z.C., R.T, and M.W. analyzed the data. W.T. produced the miR-379KO mice. F.-M.L., M.K., Z.B.C., and Z.C. analyzed RNA-seq and hybrid-seq results. D.C. helped with the mitochondria function experiments, J.H. with the Seahorse experiments, and P.T.F. with the mouse metabolic phenotyping. M.K., M.A., and R.N. wrote and edited the manuscript. All authors have read and discussed the manuscript. \n\nThe authors declare no competing interests.\n\nKato, M., Abdollahi, M., Tunduguru, R. et al. Publisher Correction: miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1. Commun Biol 4, 175 (2021). https://doi.org/10.1038/s42003-021-01691-4\n\nPublished - s42003-020-01516-w.pdf
Supplemental Material - 42003_2020_1516_MOESM1_ESM.pdf
Supplemental Material - 42003_2020_1516_MOESM2_ESM.pdf
Supplemental Material - 42003_2020_1516_MOESM3_ESM.xls
Supplemental Material - 42003_2020_1516_MOESM4_ESM.xls
Erratum - s42003-021-01691-4.pdf
", "abstract": "Diabetic kidney disease (DKD) is a major complication of diabetes. Expression of members of the microRNA (miRNA) miR-379 cluster is increased in DKD. miR-379, the most upstream 5\u2032-miRNA in the cluster, functions in endoplasmic reticulum (ER) stress by targeting EDEM3. However, the in vivo functions of miR-379 remain unclear. We created miR-379 knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique and characterized their phenotype in diabetes. We screened for miR-379 targets in renal mesangial cells from WT vs. miR-379KO mice using AGO2-immunopreciptation and CLASH (cross-linking, ligation, sequencing hybrids) and identified the redox protein thioredoxin and mitochondrial fission-1 protein. miR-379KO mice were protected from features of DKD as well as body weight loss associated with mitochondrial dysfunction, ER- and oxidative stress. These results reveal a role for miR-379 in DKD and metabolic processes via reducing adaptive mitophagy. Strategies targeting miR-379 could offer therapeutic options for DKD.", "date": "2021-01-04", "date_type": "published", "publication": "Communications Biology", "volume": "4", "publisher": "Springer Nature", "pagerange": "Art. No. 30", "id_number": "CaltechAUTHORS:20210107-094647288", "issn": "2399-3642", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210107-094647288", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 DK081705" }, { "agency": "NIH", "grant_number": "R01 DK058191" }, { "agency": "NIH", "grant_number": "R01 HL106089" }, { "agency": "City of Hope" }, { "agency": "NIH", "grant_number": "R01HL145170" }, { "agency": "American Diabetes Association", "grant_number": "ADA-1-18-IBS-103" }, { "agency": "Larry L. Hillblom Foundation" }, { "agency": "NIH", "grant_number": "P30CA33572" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s42003-020-01516-w", "pmcid": "PMC7782535", "primary_object": { "basename": "s42003-021-01691-4.pdf", "url": "https://authors.library.caltech.edu/records/t7h7v-1wr36/files/s42003-021-01691-4.pdf" }, "related_objects": [ { "basename": "42003_2020_1516_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/t7h7v-1wr36/files/42003_2020_1516_MOESM1_ESM.pdf" }, { "basename": "42003_2020_1516_MOESM2_ESM.pdf", "url": "https://authors.library.caltech.edu/records/t7h7v-1wr36/files/42003_2020_1516_MOESM2_ESM.pdf" }, { "basename": "42003_2020_1516_MOESM3_ESM.xls", "url": "https://authors.library.caltech.edu/records/t7h7v-1wr36/files/42003_2020_1516_MOESM3_ESM.xls" }, { "basename": "42003_2020_1516_MOESM4_ESM.xls", "url": "https://authors.library.caltech.edu/records/t7h7v-1wr36/files/42003_2020_1516_MOESM4_ESM.xls" }, { "basename": "s42003-020-01516-w.pdf", "url": "https://authors.library.caltech.edu/records/t7h7v-1wr36/files/s42003-020-01516-w.pdf" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Kato, Mitsuo; Abdollahi, Maryam; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/t28vw-5xa51", "eprint_id": 106463, "eprint_status": "archive", "datestamp": "2023-08-22 07:38:55", "lastmod": "2023-12-22 23:13:27", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Adachi-Yoshihiro", "name": { "family": "Adachi", "given": "Yoshihiro" } }, { "id": "Kato-Takashi", "name": { "family": "Kato", "given": "Takashi" } }, { "id": "Yamada-Tatsuya", "name": { "family": "Yamada", "given": "Tatsuya" }, "orcid": "0000-0002-6906-9861" }, { "id": "Murata-Daisuke", "name": { "family": "Murata", "given": "Daisuke" }, "orcid": "0000-0003-3829-6620" }, { "id": "Arai-Kenta", "name": { "family": "Arai", "given": "Kenta" } }, { "id": "Stahelin-Robert-V", "name": { "family": "Stahelin", "given": "Robert V." }, "orcid": "0000-0001-5443-7863" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Iijima-Mijo", "name": { "family": "Iijima", "given": "Miho" } }, { "id": "Sesaki-Hiromi", "name": { "family": "Sesaki", "given": "Hiromi" }, "orcid": "0000-0002-6877-3929" } ] }, "title": "Drp1 Tubulates the ER in a GTPase-Independent Manner", "ispublished": "pub", "full_text_status": "public", "keywords": "mitochondria; the endoplasmic reticulum; Drp1; organelle contact sites; phosphaditic acid; mitochondrial division", "note": "\u00a9 2020 Elsevier. \n\nReceived 28 April 2020, Revised 10 September 2020, Accepted 9 October 2020, Available online 4 November 2020. \n\nWe thank past and present members of the Iijima and Sesaki labs for helpful discussions and technical assistance. We are grateful to Dr. H. Otera for providing Drp1-KO and Mff/Fis1 double-KO Hela cells and Dr. A. van der Bliek for anti-Mff antibodies. This work was supported by NIH grants to M.I. (GM131768) and H.S. (GM123266 and GM130695), a grant from Diana Helis Henry Medical Research Foundation and Adrienne Helis Malvin Medical Research Foundation to H.S., and a grant from Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation to H.S. \n\nAuthor Contributions. Y.A., M.I., and H.S. conceived the project. Y.A., T.K., T.Y., D.M., and M.I. performed the experiments. Y.A., K.A., R.V.S., M.I., and H.S. analyzed the data. D.C.C. provided critical reagents. Y.A., T.K., T.Y., K.A., D.M., R.V.S., D.C.C., M.I., and H.S. contributed to discussions. Y.A., M.I., and H.S. wrote the manuscript. \n\nThe authors declare no competing interests.\n\nAccepted Version - nihms-1639300.pdf
Supplemental Material - 1-s2.0-S1097276520307206-mmc1.pdf
", "abstract": "Mitochondria are highly dynamic organelles that continuously grow, divide, and fuse. The division of mitochondria is crucial for human health. During mitochondrial division, the mechano-guanosine triphosphatase (GTPase) dynamin-related protein (Drp1) severs mitochondria at endoplasmic reticulum (ER)-mitochondria contact sites, where peripheral ER tubules interact with mitochondria. Here, we report that Drp1 directly shapes peripheral ER tubules in human and mouse cells. This ER-shaping activity is independent of GTP hydrolysis and located in a highly conserved peptide of 18 amino acids (termed D-octadecapeptide), which is predicted to form an amphipathic \u03b1 helix. Synthetic D-octadecapeptide tubulates liposomes in vitro and the ER in cells. ER tubules formed by Drp1 promote mitochondrial division by facilitating ER-mitochondria interactions. Thus, Drp1 functions as a two-in-one protein during mitochondrial division, with ER tubulation and mechano-GTPase activities.", "date": "2020-11-19", "date_type": "published", "publication": "Molecular Cell", "volume": "80", "number": "4", "publisher": "Cell Press", "pagerange": "621-632", "id_number": "CaltechAUTHORS:20201105-160425351", "issn": "1097-2765", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201105-160425351", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM131768" }, { "agency": "NIH", "grant_number": "GM123266" }, { "agency": "NIH", "grant_number": "GM130695" }, { "agency": "Adrienne Helis Malvin Medical Research Foundation" }, { "agency": "Diana Helis Henry Medical Research Foundation" }, { "agency": "Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.molcel.2020.10.013", "pmcid": "PMC7680448", "primary_object": { "basename": "1-s2.0-S1097276520307206-mmc1.pdf", "url": "https://authors.library.caltech.edu/records/t28vw-5xa51/files/1-s2.0-S1097276520307206-mmc1.pdf" }, "related_objects": [ { "basename": "nihms-1639300.pdf", "url": "https://authors.library.caltech.edu/records/t28vw-5xa51/files/nihms-1639300.pdf" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Adachi, Yoshihiro; Kato, Takashi; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/nwt2x-ydr24", "eprint_id": 104428, "eprint_status": "archive", "datestamp": "2023-08-19 22:07:56", "lastmod": "2023-12-22 23:13:29", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Varuzhanyan-G", "name": { "family": "Varuzhanyan", "given": "Grigor" }, "orcid": "0000-0001-6165-0857" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial dynamics during spermatogenesis", "ispublished": "pub", "full_text_status": "public", "keywords": "Membrane fission, Membrane fusion, Mitochondrial dynamics, Spermatogenesis", "note": "\u00a9 2020 Published by The Company of Biologists Ltd. \n\nWe thank all members of the Chan laboratory for helpful discussions and for comments on the manuscript. \n\nThe authors declare no competing or financial interests. \n\nWork in the laboratory of D.C.C. is funded by the National Institutes of Health (R35GM127147A). Deposited in PMC for release after 12 months.\n\nPublished - jcs235937.full.pdf
", "abstract": "Mitochondrial fusion and fission (mitochondrial dynamics) are homeostatic processes that safeguard normal cellular function. This relationship is especially strong in tissues with constitutively high energy demands, such as brain, heart and skeletal muscle. Less is known about the role of mitochondrial dynamics in developmental systems that involve changes in metabolic function. One such system is spermatogenesis. The first mitochondrial dynamics gene, Fuzzy onions (Fzo), was discovered in 1997 to mediate mitochondrial fusion during Drosophila spermatogenesis. In mammals, however, the role of mitochondrial fusion during spermatogenesis remained unknown for nearly two decades after discovery of Fzo. Mammalian spermatogenesis is one of the most complex and lengthy differentiation processes in biology, transforming spermatogonial stem cells into highly specialized sperm cells over a 5-week period. This elaborate differentiation process requires several developmentally regulated mitochondrial and metabolic transitions, making it an attractive model system for studying mitochondrial dynamics in vivo. We review the emerging role of mitochondrial biology, and especially its dynamics, during the development of the male germ line.", "date": "2020-07", "date_type": "published", "publication": "Journal of Cell Science", "volume": "133", "number": "14", "publisher": "Company of Biologists", "pagerange": "Art. No. jcs235937", "id_number": "CaltechAUTHORS:20200717-104855196", "issn": "0021-9533", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200717-104855196", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R35GM127147A" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1242/jcs.235937", "pmcid": "PMC7375475", "primary_object": { "basename": "jcs235937.full.pdf", "url": "https://authors.library.caltech.edu/records/nwt2x-ydr24/files/jcs235937.full.pdf" }, "resource_type": "article", "pub_year": "2020", "author_list": "Varuzhanyan, Grigor and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/qp5zm-q5k12", "eprint_id": 99244, "eprint_status": "archive", "datestamp": "2023-08-19 19:21:13", "lastmod": "2023-10-18 18:10:10", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial Dynamics and Its Involvement in Disease", "ispublished": "pub", "full_text_status": "restricted", "keywords": "mitochondrial dynamics, mitochondrial fusion, mitochondrial fission, mitophagy, neurodegeneration", "note": "\u00a9 2019 Annual Reviews. \n\nReview in Advance first posted online on October 4, 2019. \n\nThe author is grateful to Hsiuchen Chen for insightful comments on this manuscript. Work in the author's laboratory is supported by the National Institutes of Health (GM119388 and GM124147). \n\nThe author is not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.", "abstract": "The dynamic properties of mitochondria\u2014including their fusion, fission, and degradation\u2014are critical for their optimal function in energy generation. The interplay of fusion and fission confers widespread benefits on mitochondria, including efficient transport, increased homogenization of the mitochondrial population, and efficient oxidative phosphorylation. These benefits arise through control of morphology, content exchange, equitable inheritance of mitochondria, maintenance of high-quality mitochondrial DNA, and segregation of damaged mitochondria for degradation. The key components of the machinery mediating mitochondrial fusion and fission belong to the dynamin family of GTPases that utilize GTP hydrolysis to drive mechanical work on biological membranes. Defects in this machinery cause a range of diseases that especially affect the nervous system. In addition, several common diseases, including neurodegenerative diseases and cancer, strongly affect mitochondrial dynamics.", "date": "2020-01", "date_type": "published", "publication": "Annual Review of Pathology: Mechanisms of Disease", "volume": "15", "publisher": "Annual Reviews", "pagerange": "235-259", "id_number": "CaltechAUTHORS:20191014-080340305", "issn": "1553-4006", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191014-080340305", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM119388" }, { "agency": "NIH", "grant_number": "GM124147" } ] }, "doi": "10.1146/annurev-pathmechdis-012419-032711", "resource_type": "article", "pub_year": "2020", "author_list": "Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/yce3r-mnc08", "eprint_id": 106387, "eprint_status": "archive", "datestamp": "2023-08-19 19:05:14", "lastmod": "2023-10-20 23:25:55", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Mishra-Prashant", "name": { "family": "Mishra", "given": "Prashant" } }, { "id": "Zhang-Ting", "name": { "family": "Zhang", "given": "Ting" } }, { "id": "Guo-Ming", "name": { "family": "Guo", "given": "Ming" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial Respiratory Measurements in Patient-derived Fibroblasts", "ispublished": "pub", "full_text_status": "public", "keywords": "Patient-derived fibroblasts, Mitochondrial respiration, Seahorse XF assay, Inclusion body myopathy, Paget disease and frontotemporal dementia (IBMPFD), VCP/p97", "note": "\u00a9 2019 Mishra et al. This article is distributed under the terms of the Creative Commons Attribution License (CC BY 4.0). \n\nWe are grateful to the generous support from the National Institute of Health (National Institute on Aging), Glenn Foundation for Medical Research, the Natalie R. and Eugene S. Jones Fund in Aging and Neurodegenerative Disease Research, Kenneth Glenn Family Foundation, funds from the UCLA Laurie and Steven Gordon Commitment to Cure Parkinson's Disease, and Renee and Meyer Luskin Family Fund. \n\nWe have no competing interests.\n\nPublished - Bio-protocol3446.pdf
", "abstract": "Mitochondrial dysfunction is associated with a number of human diseases. As an example, we recently established in vivo Drosophila models of IBMPFD (Inclusion body myopathy, Paget disease, and frontotemporal dementia), and uncovered that human disease mutations of the p97/VCP (Valosin Containing Protein) gene behave as hyperactive alleles associated with mitochondrial defects. Pharmacologic inhibition of VCP strongly suppressed disease and mitochondrial pathology in these animal models. In this protocol, we describe a method to evaluate mitochondrial respiratory function in IBMPFD patient-derived fibroblasts, as well as investigate the role of pharmacologic treatments. These experiments complement work done in animal models by investigating mitochondrial biology and the pharmacologic response in a human cell-based model of the disease. In principle, this technique can be used to investigate mitochondrial respiratory function for any disease in which patient-derived fibroblasts are available.", "date": "2019-12-05", "date_type": "published", "publication": "Bio-protocol", "volume": "9", "number": "23", "publisher": "Bio-Protocol", "pagerange": "Art. No. e3446", "id_number": "CaltechAUTHORS:20201103-072654229", "issn": "2331-8325", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201103-072654229", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH" }, { "agency": "Glenn Foundation for Medical Research" }, { "agency": "Natalie R. and Eugene S. Jones Fund in Aging and Neurodegenerative Disease Research" }, { "agency": "Kenneth Glenn Family Foundation" }, { "agency": "UCLA" }, { "agency": "Renee and Meyer Luskin Family Fund" } ] }, "doi": "10.21769/bioprotoc.3446", "pmcid": "PMC7853990", "primary_object": { "basename": "Bio-protocol3446.pdf", "url": "https://authors.library.caltech.edu/records/yce3r-mnc08/files/Bio-protocol3446.pdf" }, "resource_type": "article", "pub_year": "2019", "author_list": "Mishra, Prashant; Zhang, Ting; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/9hdcm-s1k10", "eprint_id": 99676, "eprint_status": "archive", "datestamp": "2023-08-22 02:47:15", "lastmod": "2023-10-18 18:39:25", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-Yu-Jie", "name": { "family": "Li", "given": "Yu-Jie" }, "orcid": "0000-0002-8425-386X" }, { "id": "Cao-Yu-Lu", "name": { "family": "Cao", "given": "Yu-Lu" }, "orcid": "0000-0002-5239-1184" }, { "id": "Feng-Jian-Xiong", "name": { "family": "Feng", "given": "Jian-Xiong" } }, { "id": "Qi-Yuanbo", "name": { "family": "Qi", "given": "Yuanbo" }, "orcid": "0000-0002-6589-3677" }, { "id": "Meng-Shuxia", "name": { "family": "Meng", "given": "Shuxia" } }, { "id": "Yang-Jie-Feng", "name": { "family": "Yang", "given": "Jie-Feng" } }, { "id": "Zhong-Ya-Ting", "name": { "family": "Zhong", "given": "Ya-Ting" } }, { "id": "Kang-Sisi", "name": { "family": "Kang", "given": "Sisi" } }, { "id": "Chen-Xiaoxue", "name": { "family": "Chen", "given": "Xiaoxue" } }, { "id": "Lan-Lan", "name": { "family": "Lan", "given": "Lan" } }, { "id": "Luo-Li", "name": { "family": "Luo", "given": "Li" } }, { "id": "Yu-Bing", "name": { "family": "Yu", "given": "Bing" } }, { "id": "Chen-Shoudeng", "name": { "family": "Chen", "given": "Shoudeng" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Hu-Junjie", "name": { "family": "Hu", "given": "Junjie" }, "orcid": "0000-0003-4712-2243" }, { "id": "Gao-Song", "name": { "family": "Gao", "given": "Song" }, "orcid": "0000-0001-7427-6681" } ] }, "title": "Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset", "ispublished": "pub", "full_text_status": "public", "keywords": "Enzyme mechanisms; Mitochondria; Neurodegenerative diseases; X-ray crystallography", "note": "\u00a9 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \n\nReceived 02 April 2019; Accepted 02 October 2019; Published 29 October 2019. \n\nData availability: Data supporting the findings of this paper are available from the corresponding author upon reasonable request. A reporting summary for this article is available as a Supplementary Information file. The source data underlying Figs. 2a, d, 4h, 5b\u2013f, 6b, a and Supplementary Figs. 3e, 4a, 5f, 6e, f, 7b, c are provided as a Source Data file. The X-ray crystallographic coordinates and structure factor files for MFN2IM structures have been deposited in the Protein Data Bank (PDB) under the following accession numbers: 6JFL for nucleotide-free MFN2IM, 6JFK for GDP-bound MFN2IM, and 6JFM for MFN2IM(T111D). \n\nWe thank the staff of SSRF for the help with the collection of crystal diffraction data, Prof Tengchuan Jin for sharing the MBP plasmids, and Prof Oliver Daumke for the comments on the paper. This work was supported by following grants: National Key R&D Program of China to S.G. (2018YFA0508300), National Natural Science Foundation of China to S.G. (31722016, 31470729, and 81772977) and to Y.-L.C. (81802730), Natural Science Foundation of Guangdong Province to S.G. (2014TQ01R584 and 2014A030312015), Innovative Team Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory to S.G. (2018GZR110103002), the National Institutes of Health to D.C.C. (GM110039 and GM119388). \n\nAuthor Contributions: S.G. and Y.-L.C. conceived the project. Y,-J.L, and Y.-L.C. made the constructs, and solved structures. Y,-J.L. and J.-X.F. purified proteins, performed crystallographic, and most of the biochemical experiments. Y.Q. and L.L. carried out analytical ultracentrifugation and FRET experiments. S.M. did mitochondrial elongation assays. J.-F.Y. did native PAGE experiments, Y.-T.Z., L.L., S.K., X.C. and B.Y. helped with protein purification and biochemical experiments. S.C., Y.-L.C., J.H, D.C.C. and S.G. analyzed data. S.G. wrote the paper. \n\nThe authors declare no competing interests.\n\nPublished - s41467-019-12912-0.pdf
Supplemental Material - 41467_2019_12912_MOESM1_ESM.pdf
Supplemental Material - 41467_2019_12912_MOESM2_ESM.pdf
Supplemental Material - 41467_2019_12912_MOESM3_ESM.xlsx
", "abstract": "Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease.", "date": "2019-10-29", "date_type": "published", "publication": "Nature Communications", "volume": "10", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 4914", "id_number": "CaltechAUTHORS:20191105-105608947", "issn": "2041-1723", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191105-105608947", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Key Research and Development Program of China", "grant_number": "2018YFA0508300" }, { "agency": "National Natural Science Foundation of China", "grant_number": "31722016" }, { "agency": "National Natural Science Foundation of China", "grant_number": "31470729" }, { "agency": "National Natural Science Foundation of China", "grant_number": "81772977" }, { "agency": "National Natural Science Foundation of China", "grant_number": "81802730" }, { "agency": "Natural Science Foundation of Guangdong Province", "grant_number": "2014TQ01R584" }, { "agency": "Natural Science Foundation of Guangdong Province", "grant_number": "2014A030312015" }, { "agency": "Guangzhou Regenerative Medicine and Health Guangdong Laboratory", "grant_number": "2018GZR110103002" }, { "agency": "NIH", "grant_number": "GM110039" }, { "agency": "NIH", "grant_number": "GM119388" } ] }, "doi": "10.1038/s41467-019-12912-0", "pmcid": "PMC6820788", "primary_object": { "basename": "s41467-019-12912-0.pdf", "url": "https://authors.library.caltech.edu/records/9hdcm-s1k10/files/s41467-019-12912-0.pdf" }, "related_objects": [ { "basename": "41467_2019_12912_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/9hdcm-s1k10/files/41467_2019_12912_MOESM1_ESM.pdf" }, { "basename": "41467_2019_12912_MOESM2_ESM.pdf", "url": "https://authors.library.caltech.edu/records/9hdcm-s1k10/files/41467_2019_12912_MOESM2_ESM.pdf" }, { "basename": "41467_2019_12912_MOESM3_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/9hdcm-s1k10/files/41467_2019_12912_MOESM3_ESM.xlsx" } ], "resource_type": "article", "pub_year": "2019", "author_list": "Li, Yu-Jie; Cao, Yu-Lu; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/t5avf-xd622", "eprint_id": 99250, "eprint_status": "archive", "datestamp": "2023-08-19 18:15:52", "lastmod": "2023-10-18 18:10:33", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Varuzhanyan-G", "name": { "family": "Varuzhanyan", "given": "Grigor" }, "orcid": "0000-0001-6165-0857" }, { "id": "Rojansky-R", "name": { "family": "Rojansky", "given": "Rebecca" } }, { "id": "Sweredoski-M-J", "name": { "family": "Sweredoski", "given": "Michael J." }, "orcid": "0000-0003-0878-3831" }, { "id": "Graham-R-L-J", "name": { "family": "Graham", "given": "Robert L. J." } }, { "id": "Hess-S", "name": { "family": "Hess", "given": "Sonja" }, "orcid": "0000-0002-5904-9816" }, { "id": "Ladinsky-M-S", "name": { "family": "Ladinsky", "given": "Mark S." }, "orcid": "0000-0002-1036-3513" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial fusion is required for spermatogonial differentiation and meiosis", "ispublished": "pub", "full_text_status": "public", "keywords": "mitochondrial fusion, mitofusins, spermatogenesis, meiosis, mitochondria", "note": "\u00a9 2019, Varuzhanyan et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited. \n\nReceived: 04 September 2019; Accepted: 27 September 2019; Published: 09 October 2019. \n\nWe thank Hsiuchen Chen for her initial characterization of S8::Mfn1 and S8::Mfn2 mice, for help with maintaining mouse colonies, and for overall guidance throughout the project. We thank Safia Malki and Alex Bortvin for providing a detailed protocol for chromosomal spreading and with help identifying germ cell-specific markers; Prabhakara P. Reddi for providing the SP-10 antibody; and Jared Rutter for advice on studying MPC1. We thank all members of the Chan Lab for helpful discussions and for comments on the manuscript. Grigor Varuzhanyan was supported by a National Science Foundation Graduate Research Fellowship (DGE\u20101144469) and a National Institutes of Health Cell and Molecular Biology Training Grant (GM07616T32). Sonja Hess and Robert LJ Graham were supported by grants from the Gordon and Betty Moore Foundation through GBMF775 and the Beckman Institute. This work was supported by NIH grants GM119388 and GM127147. \n\nThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. \n\nThe authors declare no competing interests. \n\nEthics: Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the California Institute of Technology. \n\nData availability: All data generated or analyzed during this study are included in the manuscript and supporting files.\n\nPublished - elife-51601-v2.pdf
Supplemental Material - elife-51601-supp1-v2.xlsx
Supplemental Material - elife-51601-supp2-v2.xlsx
Supplemental Material - elife-51601-transrepform-v2.pdf
", "abstract": "Differentiating cells tailor their metabolism to fulfill their specialized functions. We examined whether mitochondrial fusion is important for metabolic tailoring during spermatogenesis. Acutely after depletion of mitofusins Mfn1 and Mfn2, spermatogenesis arrests due to failure to accomplish a metabolic shift during meiosis. This metabolic shift includes increased mitochondrial content, mitochondrial elongation, and upregulation of oxidative phosphorylation (OXPHOS). With long-term mitofusin loss, all differentiating germ cell types are depleted, but proliferation of stem-like undifferentiated spermatogonia remains unaffected. Thus, compared with undifferentiated spermatogonia, differentiating spermatogonia and meiotic spermatocytes have cell physiologies that require high levels of mitochondrial fusion. Proteomics in fibroblasts reveals that mitofusin-null cells downregulate respiratory chain complexes and mitochondrial ribosomal subunits. Similarly, mitofusin depletion in immortalized spermatocytes or germ cells in vivo results in reduced OXPHOS subunits and activity. We reveal that by promoting OXPHOS, mitofusins enable spermatogonial differentiation and a metabolic shift during meiosis.", "date": "2019-10-09", "date_type": "published", "publication": "eLife", "volume": "8", "publisher": "eLife Sciences Publications", "pagerange": "Art. No. e51601", "id_number": "CaltechAUTHORS:20191014-105658223", "issn": "2050-084X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191014-105658223", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE\u20101144469" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "GM07616T32" }, { "agency": "Gordon and Betty Moore Foundation", "grant_number": "GBMF775" }, { "agency": "Caltech Beckman Institute" }, { "agency": "NIH", "grant_number": "GM119388" }, { "agency": "NIH", "grant_number": "GM127147" } ] }, "doi": "10.7554/elife.51601", "pmcid": "PMC6805159", "primary_object": { "basename": "elife-51601-supp1-v2.xlsx", "url": "https://authors.library.caltech.edu/records/t5avf-xd622/files/elife-51601-supp1-v2.xlsx" }, "related_objects": [ { "basename": "elife-51601-supp2-v2.xlsx", "url": "https://authors.library.caltech.edu/records/t5avf-xd622/files/elife-51601-supp2-v2.xlsx" }, { "basename": "elife-51601-transrepform-v2.pdf", "url": "https://authors.library.caltech.edu/records/t5avf-xd622/files/elife-51601-transrepform-v2.pdf" }, { "basename": "elife-51601-v2.pdf", "url": "https://authors.library.caltech.edu/records/t5avf-xd622/files/elife-51601-v2.pdf" } ], "resource_type": "article", "pub_year": "2019", "author_list": "Varuzhanyan, Grigor; Rojansky, Rebecca; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/w84hn-p3v59", "eprint_id": 92973, "eprint_status": "archive", "datestamp": "2023-08-19 14:20:44", "lastmod": "2023-10-20 16:41:48", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kehr-A-D", "name": { "family": "Kehr", "given": "Andrew D." } }, { "id": "Meng-Shuxia", "name": { "family": "Meng", "given": "Shuxia" } }, { "id": "Martin-M-F", "name": { "family": "Martin", "given": "Matthew F." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" }, { "id": "Hinshaw-J-E", "name": { "family": "Hinshaw", "given": "Jenny E." } } ] }, "title": "Advances in the Structural and Biochemical Determination of Several Dynamin-Like GTPases", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2019 Biophysical Society. \n\nAvailable online 15 February 2019.", "abstract": "Dynamins are a class of GTPase enzymes responsible for the fusion, fission, and vesiculation of lipid membranes throughout the cell. The dynamin-like protein Optic Atrophy 1 (Opa1) is responsible for the fusion of the mitochondrial inner membrane and plays a role in maintaining cristae shape. Atlastin mediates fusion of homotypic three-way junctions in the endoplasmic reticulum (ER). Mutations in these, and other dynamin-like proteins, can lead to neuropathies including Dominant Optic Atrophy, Hereditary Spastic Paraplegia, and Charcot-Marie-Tooth, among others. Currently, structural and biochemical data is limiting for Opa1. In addition, crystal structures of ATL with nucleotide do not entirely explain the GTPase cycle. We have developed a protocol for expressing and purifying biologically relevant and biochemically active shortened isoforms of Opa1 (Opa1GG) in sufficient quantity to begin crystallography and biochemical assays. Furthermore, we have optimized sample prep and begun reconstructions of aproteolytically processed short form, Opa1S, by cryo-EM on a lipid surface and are examining the role nucleotide plays in structural rearrangements. In addition, to verify work performed by x-ray crystallography, we have begun probing the GTPase cycle of Atlastin using single particle cryo-EM methods.", "date": "2019-02-15", "date_type": "published", "publication": "Biophysical Journal", "volume": "116", "number": "3", "publisher": "Biophysical Society", "pagerange": "473a", "id_number": "CaltechAUTHORS:20190219-111416959", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190219-111416959", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.bpj.2018.11.2552", "resource_type": "article", "pub_year": "2019", "author_list": "Kehr, Andrew D.; Meng, Shuxia; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/vb8fz-8gb39", "eprint_id": 88601, "eprint_status": "archive", "datestamp": "2023-08-22 00:05:42", "lastmod": "2023-10-18 22:10:31", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Del-Dotto-Valentina", "name": { "family": "Del Dotto", "given": "Valentina" } }, { "id": "Fogazza-Mario", "name": { "family": "Fogazza", "given": "Mario" } }, { "id": "Musiani-Francesco", "name": { "family": "Musiani", "given": "Francesco" } }, { "id": "Maresca-Alessandra", "name": { "family": "Maresca", "given": "Alessandra" }, "orcid": "0000-0002-8959-8832" }, { "id": "Aleo-Serena-J", "name": { "family": "Aleo", "given": "Serena J." } }, { "id": "Caporali-Leonardo", "name": { "family": "Caporali", "given": "Leonardo" } }, { "id": "La-Morgia-Chiara", "name": { "family": "La Morgia", "given": "Chiara" } }, { "id": "Nolli-Cecilia", "name": { "family": "Nolli", "given": "Cecilia" } }, { "id": "Lodi-Tiziana", "name": { "family": "Lodi", "given": "Tiziana" } }, { "id": "Goffrini-Paola", "name": { "family": "Goffrini", "given": "Paola" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" }, { "id": "Carelli-Valerio", "name": { "family": "Carelli", "given": "Valerio" } }, { "id": "Rugulo-Michela", "name": { "family": "Rugulo", "given": "Michela" } }, { "id": "Baruffini-Enrico", "name": { "family": "Baruffini", "given": "Enrico" } }, { "id": "Zanna-Claudia", "name": { "family": "Zanna", "given": "Claudia" } } ] }, "title": "Deciphering OPA1 mutations pathogenicity by combined analysis of human, mouse and yeast cell models", "ispublished": "pub", "full_text_status": "public", "keywords": "OPA1 mutations; Dominant Optic Atrophy (DOA); OPA1; Mitochondrial network; mtDNA; Mitochondrial functions", "note": "\u00a9 2018 Elsevier. \n\nReceived 12 January 2018, Revised 24 July 2018, Accepted 1 August 2018, Available online 4 August 2018. \n\nThis work was supported by the Futuro in Ricerca FIR2013 from the Ministero della Istruzione Universit\u00e0 e Ricerca (MIUR) [RBFR131WDS-001 to CZ and RBFR131WDS-002 to EB]; and the National Institutes of Health [GM110039 to DCC]. We thank Mirca Lazzaretti for the helpful technical assistance with the fluorescence microscope in yeast. \n\nThe authors declare no financial conflict of interest that might be construed to influence the results or interpretation of the manuscript. \n\nAuthors contributions: Conceptualization, VDD, EB and CZ; Methodology, VDD, EB and CZ; Investigation, VDD, MF, FM, AM, SJA, LC, CLM, CN, EB and CZ; Resources, DC; Writing \u2013 Original Draft, VDD, EB and CZ; Writing \u2013 Review & Editing, VDD, TL, PG, DC, VC, MR, EB and CZ; Visualization, VDD, EB and CZ; Funding Acquisition, DC and CZ; Supervision, MR, TL, PG, EB and CZ; Project Administration, EB and CZ.\n\nSupplemental Material - 1-s2.0-S0925443918302898-mmc2.docx
", "abstract": "OPA1 is the major gene responsible for Dominant Optic Atrophy (DOA) and the syndromic form DOA \"plus\". Over 370 OPA1 mutations have been identified so far, although their pathogenicity is not always clear. We have analyzed one novel and a set of known OPA1 mutations to investigate their impact on protein functions in primary skin fibroblasts and in two \"ad hoc\" generated cell systems: the MGM1/OPA1 chimera yeast model and the Opa1\u2212/\u2212 MEFs model expressing the mutated human OPA1 isoform 1. The yeast model allowed us to confirm the deleterious effects of these mutations and to gain information on their dominance/recessivity. The MEFs model enhanced the phenotypic alteration caused by mutations, nicely correlating with the clinical severity observed in patients, and suggested that the DOA \"plus\" phenotype could be induced by the combinatorial effect of mitochondrial network fragmentation with variable degrees of mtDNA depletion. Overall, the two models proved to be valuable tools to functionally assess and define the deleterious mechanism and the pathogenicity of novel OPA1 mutations, and useful to testing new therapeutic interventions.", "date": "2018-10", "date_type": "published", "publication": "Biochimica et Biophysica Acta - Molecular Basis of Disease", "volume": "1864", "number": "10", "publisher": "Elsevier", "pagerange": "3496-3514", "id_number": "CaltechAUTHORS:20180806-125015141", "issn": "0925-4439", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180806-125015141", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Ministero dell'Istruzione, dell'Universit\u00e0 e della Ricerca (MIUR)", "grant_number": "RBFR131WDS-001" }, { "agency": "Ministero dell'Istruzione, dell'Universit\u00e0 e della Ricerca (MIUR)", "grant_number": "RBFR131WDS-002" }, { "agency": "NIH", "grant_number": "GM110039" } ] }, "doi": "10.1016/j.bbadis.2018.08.004", "primary_object": { "basename": "1-s2.0-S0925443918302898-mmc2.docx", "url": "https://authors.library.caltech.edu/records/vb8fz-8gb39/files/1-s2.0-S0925443918302898-mmc2.docx" }, "resource_type": "article", "pub_year": "2018", "author_list": "Del Dotto, Valentina; Fogazza, Mario; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/7ah5s-tr102", "eprint_id": 90055, "eprint_status": "archive", "datestamp": "2023-08-19 11:33:35", "lastmod": "2023-10-18 23:10:18", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Guo-Yuxuan", "name": { "family": "Guo", "given": "Yuxuan" }, "orcid": "0000-0002-6009-4403" }, { "id": "Jardin-B-D", "name": { "family": "Jardin", "given": "Blake D." }, "orcid": "0000-0002-1376-5235" }, { "id": "Zhou-Pingzhu", "name": { "family": "Zhou", "given": "Pingzhu" } }, { "id": "Sethi-I", "name": { "family": "Sethi", "given": "Isha" } }, { "id": "Akerberg-B-N", "name": { "family": "Akerberg", "given": "Brynn N." } }, { "id": "Toepfer-C-N", "name": { "family": "Toepfer", "given": "Christopher N." }, "orcid": "0000-0003-4671-2030" }, { "id": "Ai-Yulan", "name": { "family": "Ai", "given": "Yulan" } }, { "id": "Li-Yifei", "name": { "family": "Li", "given": "Yifei" }, "orcid": "0000-0002-3096-4287" }, { "id": "Ma-Qing", "name": { "family": "Ma", "given": "Qing" } }, { "id": "Guatimosim-S", "name": { "family": "Guatimosim", "given": "Silvia" } }, { "id": "Hu-Yongwu", "name": { "family": "Hu", "given": "Yongwu" } }, { "id": "Varuzhanyan-G", "name": { "family": "Varuzhanyan", "given": "Grigor" }, "orcid": "0000-0001-6165-0857" }, { "id": "VanDusen-N-J", "name": { "family": "VanDusen", "given": "Nathan J." } }, { "id": "Zhang-Donghui", "name": { "family": "Zhang", "given": "Donghui" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Yuan-Guo-Cheng", "name": { "family": "Yuan", "given": "Guo-Cheng" }, "orcid": "0000-0002-2283-4714" }, { "id": "Seidman-C-E", "name": { "family": "Seidman", "given": "Christine E." }, "orcid": "0000-0001-6380-1209" }, { "id": "Seidman-J-G", "name": { "family": "Seidman", "given": "Jonathan G." } }, { "id": "Pu-William-T", "name": { "family": "Pu", "given": "William T." }, "orcid": "0000-0002-4551-8079" } ] }, "title": "Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \n\nReceived: 14 February 2018 Accepted: 30 August 2018. Published online: 21 September 2018. \n\nWe thank the HMS EM core, HMS biopolymers core, and DFCI flow cytometry core for technical support. We also thank Drs. Joe Miano and Ivan Moskowitz for sharing the Srf-flox and Tbx5-flox mice, respectively. This work was supported by funding from NIH NHLBI (2UM1 HL098166 and U01HL131003), the American Heart Association (AHA) (17IRG33410894), and charitable support from the Boston Children's Hospital Department of Cardiology. S.G. was a recipient of a Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior fellowship and funded by Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico and Funda\u00e7\u00e3o de Amparo a Pesquisa do Estado de Minas Gerais. C.N.T. is a recipient of Sir Henry Wellcome Postdoctoral Fellowship 206466/Z/17/Z. Y.G. is a recipient of AHA postdoctoral fellowship 18POST33960037. \n\nAuthor Contributions: W.T.P. provided overall supervision of this project. Y.G. conceived and designed the study. Y.G., B.D.J., and Y.A. bred animals, produced AAV and performed histology, immunofluorescence, qPCR, and Western blot analysis. Y.G. and B.D.J. performed Langendorff perfusion, in situ heart imaging, flow cytometry, electron microscopy, and mitochondria analysis. Y.L. and D.Z. helped with mitochondria analysis. Y.L. and Q.M. performed echocardiogram analysis. G.V. and D.C.C helped with the analysis of mitofusin mice. N.J.V. helped with animal breeding and AAV production. Y.G. and W.T.P. performed and analyzed RNA-seq. Y.G, W.T.P., P.Z., I.S., B.N.A, and G.-C.Y. performed ChIP-seq and analyzed the data. Y.G., C.N.T., C.E.S., and J.G.S. performed and analyzed cell contractility. Y.G., B.D.J., and S.G. performed calcium imaging and analysis. Y.G. and W.T.P. wrote the manuscript. \n\nData availability: The authors declare that all data supporting the findings of this study are available within the article and its Supplementary information files or from the corresponding author upon reasonable request. RNA-seq and ChIP-seq data have been deposited in the Gene Expression Omnibus (GEO) database under the accession codes: GSE109425 (for the Srf KO RNA-seq), GSE109504 (ChIP-seq), and GSE116030 (for the Srf OE RNA-seq). The data are also available on the Cardiovascular Development Consortium server (https://b2b.hci.utah.edu/gnomex) (sign in as guest). \n\nThe authors declare no competing interests.\n\nPublished - s41467-018-06347-2.pdf
Supplemental Material - 41467_2018_6347_MOESM1_ESM.pdf
Supplemental Material - 41467_2018_6347_MOESM2_ESM.pdf
", "abstract": "After birth, cardiomyocytes (CM) acquire numerous adaptations in order to efficiently pump blood throughout an animal's lifespan. How this maturation process is regulated and coordinated is poorly understood. Here, we perform a CRISPR/Cas9 screen in mice and identify serum response factor (SRF) as a key regulator of CM maturation. Mosaic SRF depletion in neonatal CMs disrupts many aspects of their maturation, including sarcomere expansion, mitochondrial biogenesis, transverse-tubule formation, and cellular hypertrophy. Maintenance of maturity in adult CMs is less dependent on SRF. This stage-specific activity is associated with developmentally regulated SRF chromatin occupancy and transcriptional regulation. SRF directly activates genes that regulate sarcomere assembly and mitochondrial dynamics. Perturbation of sarcomere assembly but not mitochondrial dynamics recapitulates SRF knockout phenotypes. SRF overexpression also perturbs CM maturation. Together, these data indicate that carefully balanced SRF activity is essential to promote CM maturation through a hierarchy of cellular processes orchestrated by sarcomere assembly.", "date": "2018-09-21", "date_type": "published", "publication": "Nature Communications", "volume": "9", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 3837", "id_number": "CaltechAUTHORS:20181001-094858218", "issn": "2041-1723", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181001-094858218", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "2UM1 HL098166" }, { "agency": "NIH", "grant_number": "U01HL131003" }, { "agency": "American Heart Association", "grant_number": "17IRG33410894" }, { "agency": "Boston Children's Hospital" }, { "agency": "Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior (CAPES)" }, { "agency": "Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq)" }, { "agency": "Funda\u00e7\u00e3o de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)" }, { "agency": "Wellcome Trust", "grant_number": "206466/Z/17/Z" }, { "agency": "American Heart Association", "grant_number": "18POST33960037" } ] }, "doi": "10.1038/s41467-018-06347-2", "pmcid": "PMC6155060", "primary_object": { "basename": "41467_2018_6347_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/7ah5s-tr102/files/41467_2018_6347_MOESM1_ESM.pdf" }, "related_objects": [ { "basename": "41467_2018_6347_MOESM2_ESM.pdf", "url": "https://authors.library.caltech.edu/records/7ah5s-tr102/files/41467_2018_6347_MOESM2_ESM.pdf" }, { "basename": "s41467-018-06347-2.pdf", "url": "https://authors.library.caltech.edu/records/7ah5s-tr102/files/s41467-018-06347-2.pdf" } ], "resource_type": "article", "pub_year": "2018", "author_list": "Guo, Yuxuan; Jardin, Blake D.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/rmc9k-xqb85", "eprint_id": 86957, "eprint_status": "archive", "datestamp": "2023-08-19 11:22:15", "lastmod": "2023-10-18 20:44:10", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ryan-C-S", "name": { "family": "Ryan", "given": "Conor S." }, "orcid": "0000-0001-5400-3715" }, { "id": "Fine-A-L", "name": { "family": "Fine", "given": "Anthony L." } }, { "id": "Cohen-A-L", "name": { "family": "Cohen", "given": "Alexander L." }, "orcid": "0000-0001-6557-5866" }, { "id": "Schiltz-B-M", "name": { "family": "Schiltz", "given": "Brenda M." } }, { "id": "Renaud-D-L", "name": { "family": "Renaud", "given": "Deborah L." } }, { "id": "Wirrell-E-C", "name": { "family": "Wirrell", "given": "Elaine C." } }, { "id": "Patterson-M-C", "name": { "family": "Patterson", "given": "Marc C." } }, { "id": "Boczek-N-J", "name": { "family": "Boczek", "given": "Nicole J." } }, { "id": "Liu-Raymond", "name": { "family": "Liu", "given": "Raymond" } }, { "id": "Babovic-Vuksanovic-D", "name": { "family": "Babovic-Vuksanovic", "given": "Dusica" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Payne-E-T", "name": { "family": "Payne", "given": "Eric T." } } ] }, "title": "De Novo DNM1L Variant in a Teenager With Progressive Paroxysmal Dystonia and Lethal Super-refractory Myoclonic Status Epilepticus", "ispublished": "pub", "full_text_status": "public", "keywords": "mitochondrial disease, paroxysmal dyskinesia, rapid whole exome sequencing, refractory status epilepticus", "note": "\u00a9 2018 by SAGE Publications. \n\nReceived: January 03, 2018; Revisions received: April 25, 2018; Accepted: April 30, 2018, First Published June 7, 2018.", "abstract": "Background: The dynamin 1-like gene (DNM1L) encodes a GTPase that mediates mitochondrial and peroxisomal fission and fusion. We report a new clinical presentation associated with a DNM1L pathogenic variant and review the literature. \n\nResults: A 13-year-old boy with mild developmental delays and paroxysmal dystonia presented acutely with multifocal myoclonic super-refractory status epilepticus. Despite sustained and aggressive treatment, seizures persisted and care was ultimately withdrawn in the context of extensive global cortical atrophy. Rapid trio-whole exome sequencing revealed a de novo heterozygous c.1207C>T (p.R403C) pathogenic variant in DNM1L. Immunofluorescence staining of fibroblast mitochondria revealed abnormally elongated and tubular morphology. \n\nConclusions: This case highlights the diagnostic importance of rapid whole exome sequencing within a critical care setting and reveals the expanding phenotypic spectrum associated with DNM1L variants. This now includes progressive paroxysmal dystonia and adolescent-onset super-refractory myoclonic status epilepticus contributing to strikingly rapid and progressive cortical atrophy and death.", "date": "2018-09-01", "date_type": "published", "publication": "Journal of Child Neurology", "volume": "33", "number": "10", "publisher": "SAGE Publications", "pagerange": "651-658", "id_number": "CaltechAUTHORS:20180611-081026318", "issn": "0883-0738", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180611-081026318", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1177/0883073818778203", "resource_type": "article", "pub_year": "2018", "author_list": "Ryan, Conor S.; Fine, Anthony L.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/d9tq6-8ha42", "eprint_id": 90194, "eprint_status": "archive", "datestamp": "2023-08-19 10:35:39", "lastmod": "2023-10-18 23:16:08", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Cha-Moon-Yong", "name": { "family": "Cha", "given": "Moon Yong" } }, { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Removal of the Mitochondrial Fission Factor Mff Exacerbates Neuronal Loss and Neurological Phenotypes in a Huntington's Disease Mouse Model", "ispublished": "pub", "full_text_status": "public", "note": "Data Availability Statement:\nThe raw data for graphs in Figures 1-5 are available at https://figshare.com/s/584ca97ed838e5de3bde, with DOI: 10.6084/m9.figshare.6052007.\n\n\nCompeting Interests Statement:\nThe authors have declared that no competing interests exist.\n\nFunding:\nThis work was funded by grant A-11059 from the CHDI Foundation (https://chdifoundation.org). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nPublished - Removal_of_the_Mitochondrial_Fission_Factor_Mff_Exacerbates_Neuronal_Loss_an.pdf
", "abstract": "Objective: Excessive mitochondrial fission has been associated with several neurodegenerative diseases, including Huntington's disease (HD). Consequently, mitochondrial dynamics has been suggested to be a promising therapeutic target for Huntington's disease. Mitochondrial fission depends on recruitment of Drp1 to mitochondria, and Mff (mitochondrial fission factor) is one of the key adaptor proteins for this process. Removal of Mff therefore greatly reduces mitochondrial fission. Here we investigate whether removal of Mff can mitigate HD-associated pathologies in HD transgenic mice (R6/2) expressing mutant Htt. \n\nMethod: We compared the phenotype of HD mice with and without Mff. The mice were monitored for lifespan, neurological phenotypes, Htt aggregate formation, and brain histology.\n\nResults: We found that HD mice lacking Mff display more severe neurological phenotypes and have shortened lifespans. Loss of Mff does not affect mutant Htt aggregation, but it accelerates HD pathology, including neuronal loss and neuroinflammation.\n\nConclusions: Our data indicate a protective role for mitochondrial fission in HD and suggest that more studies are needed before manipulation of mitochondrial dynamics can be applied to HD therapy.", "date": "2018-07-26", "date_type": "published", "publication": "PLOS Currents", "publisher": "Public Library of Science", "id_number": "CaltechAUTHORS:20181009-131053999", "issn": "2157-3999", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181009-131053999", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "CHDI Foundation", "grant_number": "A-11059" } ] }, "doi": "10.1371/currents.hd.a4e15b80c4915c828d39754942c6631f", "pmcid": "PMC6149597", "primary_object": { "basename": "Removal_of_the_Mitochondrial_Fission_Factor_Mff_Exacerbates_Neuronal_Loss_an.pdf", "url": "https://authors.library.caltech.edu/records/d9tq6-8ha42/files/Removal_of_the_Mitochondrial_Fission_Factor_Mff_Exacerbates_Neuronal_Loss_an.pdf" }, "resource_type": "article", "pub_year": "2018", "author_list": "Cha, Moon Yong; Chen, Hsiuchen; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/60r4v-gxz43", "eprint_id": 86909, "eprint_status": "archive", "datestamp": "2023-08-21 23:30:18", "lastmod": "2023-10-18 20:41:33", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Jian-Fenglei", "name": { "family": "Jian", "given": "Fenglei" } }, { "id": "Chen-Dan", "name": { "family": "Chen", "given": "Dan" } }, { "id": "Chen-Li", "name": { "family": "Chen", "given": "Li" } }, { "id": "Yan-Chaojun", "name": { "family": "Yan", "given": "Chaojun" } }, { "id": "Lu-Bin", "name": { "family": "Lu", "given": "Bin" }, "orcid": "0000-0002-9036-0063" }, { "id": "Zhu-Yushan", "name": { "family": "Zhu", "given": "Yushan" } }, { "id": "Chen-Shi", "name": { "family": "Chen", "given": "Shi" } }, { "id": "Shi-Anbing", "name": { "family": "Shi", "given": "Anbing" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Song-Zhiyin", "name": { "family": "Song", "given": "Zhiyin" } } ] }, "title": "Sam50 Regulates PINK1-Parkin-Mediated Mitophagy by Controlling PINK1 Stability and Mitochondrial Morphology", "ispublished": "pub", "full_text_status": "public", "keywords": "Sam50; mitochondrial dynamics; mitophagy; PINK1-Parkin; mtDNA; gop-3", "note": "\u00a9 2018 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). \n\nReceived 20 September 2017, Revised 1 April 2018, Accepted 3 May 2018, Available online 8 June 2018. \n\nWe thank Dr. Chen Quan for the GFP-Parkin plasmid. This work was supported by the National Natural Science Foundation of China (31471264 and 31671393) and the Fundamental Research Funds for the Central Universities (2042017kf0197 and 2042017kf0242). \n\nAuthor Contributions: F.J. performed most experiments. D.C., L.C., and C.Y. performed experiments. B.L., Y.Z., S.C., and D.C.C. contributed cell lines and reagents. A.S. contributed C. elegans and designed the experiments involving C. elegans. F.J., D.C., and Z.S. prepared figures and tables. Z.S. designed the research and analyzed data. Z.S. wrote the manuscript.\n\nThe authors declare no competing interests.\n\nPublished - 1-s2.0-S2211124718307484-main.pdf
Supplemental Material - mmc1.pdf
", "abstract": "PINK1 and Parkin mediate mitophagy, the cellular process that clears dysfunctional mitochondria. Mitophagy is regulated by mitochondrial dynamics, but the molecules linking these two processes remain poorly understood. Here, we show that Sam50, the core component of the sorting and assembly machinery (SAM), is a critical regulator of mitochondrial dynamics and PINK1-Parkin-mediated mitophagy. In response to Sam50 depletion, normal tubular mitochondria are first fragmented and subsequently merged into large spheres. Sam50 interacts with PINK1 to facilitate its processing and degradation. Depletion of Sam50 results in PINK1 accumulation, Parkin recruitment, and mitophagy. Interestingly, Sam50 deficiency induces a piecemeal mode of mitophagy that eliminates mitochondria \"bit by bit\" but spares mtDNA. In C. elegans, the Sam50 homolog gop-3 is required for the maintenance of mitochondrial morphology and mass. Our findings reveal that Sam50 directly links mitochondrial dynamics and mitophagy and that Sam50 depletion induces elimination of mitochondria without affecting mtDNA content.", "date": "2018-06-05", "date_type": "published", "publication": "Cell Reports", "volume": "23", "number": "10", "publisher": "Elsevier", "pagerange": "2989-3005", "id_number": "CaltechAUTHORS:20180608-091335668", "issn": "2211-1247", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180608-091335668", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Natural Science Foundation of China", "grant_number": "31471264" }, { "agency": "National Natural Science Foundation of China", "grant_number": "31671393" }, { "agency": "Fundamental Research Funds for the Central Universities", "grant_number": "2042017kf0197" }, { "agency": "Fundamental Research Funds for the Central Universities", "grant_number": "2042017kf0242" } ] }, "doi": "10.1016/j.celrep.2018.05.015", "primary_object": { "basename": "1-s2.0-S2211124718307484-main.pdf", "url": "https://authors.library.caltech.edu/records/60r4v-gxz43/files/1-s2.0-S2211124718307484-main.pdf" }, "related_objects": [ { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/60r4v-gxz43/files/mmc1.pdf" } ], "resource_type": "article", "pub_year": "2018", "author_list": "Jian, Fenglei; Chen, Dan; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/4c2bz-2se92", "eprint_id": 86043, "eprint_status": "archive", "datestamp": "2023-08-21 23:12:50", "lastmod": "2023-10-18 19:12:53", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nemani-Neeharika", "name": { "family": "Nemani", "given": "Neeharika" } }, { "name": { "family": "Carvalho", "given": "Edmund" } }, { "name": { "family": "Tomar", "given": "Dhanendra" } }, { "name": { "family": "Dong", "given": "Zhiwei" } }, { "name": { "family": "Ketschek", "given": "Andrea" } }, { "name": { "family": "Breves", "given": "Sarah L." } }, { "name": { "family": "Ja\u00f1a", "given": "Fabi\u00e1n" } }, { "name": { "family": "Worth", "given": "Alison M." } }, { "name": { "family": "Heffler", "given": "Julie" } }, { "name": { "family": "Palaniappan", "given": "Palaniappan" } }, { "name": { "family": "Tripathi", "given": "Aparna" } }, { "name": { "family": "Subbiah", "given": "Ramasamy" } }, { "name": { "family": "Riitano", "given": "Massimo F." } }, { "name": { "family": "Seelam", "given": "Ajay" } }, { "name": { "family": "Manfred", "given": "Thomas" } }, { "name": { "family": "Itoh", "given": "Kie" } }, { "id": "Meng-Shuxia", "name": { "family": "Meng", "given": "Shuxia" } }, { "name": { "family": "Sesaki", "given": "Hiromi" } }, { "name": { "family": "Craigen", "given": "William J." } }, { "name": { "family": "Rajan", "given": "Sudarsan" } }, { "name": { "family": "Shanmughapriya", "given": "Santhanam" } }, { "name": { "family": "Caplan", "given": "Jeffrey" } }, { "name": { "family": "Prosser", "given": "Benjamin L." } }, { "name": { "family": "Gill", "given": "Donald L." } }, { "name": { "family": "Stathopulos", "given": "Peter B." } }, { "name": { "family": "Gallo", "given": "Gianluca" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "name": { "family": "Mishra", "given": "Prashant" } }, { "name": { "family": "Madesh", "given": "Muniswamy" } } ] }, "title": "MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca^(2+) Stress", "ispublished": "pub", "full_text_status": "public", "keywords": "mitochondrial shape; MiST; calcium; Miro; EF hand; PTP; MCU; mitophagy; autophagy; mitochondrial dynamics", "note": "\u00a9 2018 The Author(s). Open Access funded by National Institutes of Health. Under a Creative Commons license (CC-BY 4.0) \n\nReceived 13 March 2017, Revised 22 February 2018, Accepted 21 March 2018, Available online 25 April 2018. \n\nWe thank Craig B. Thompson, Richard Youle, Gia Voeltz, Tom Rapoport, and Gary Yellen for sharing Bax^(\u2212/\u2212)Bak^(\u2212/\u2212) MEFs, mito-Keima, mito-BFP, sec61-\u03b2, and Peredox plasmid constructs, respectively. We thank John Elrod for sharing the CypD KO MEFs. The authors also thank Shannon Modla for EM sample processing and image acquisition. This research was funded by the NIH (R01GM109882, R01HL086699, R01HL119306, and 1S10RR027327 to M.M. and R01 NS095471 to G.G.). N.N. and D.T. are supported by the AHA fellowships (17PRE33660720, 17POST33660251). S.S. is supported by a NIH K99/R00 grant (1K99HL138268-01). Z.D. is supported by China Scholarship Council (No. 201403170252). F.J. is supported by FONDECYT postdoctoral fellowship #3140458. Access to the electron microscope was supported by NIH-NIGMS (P20 GM103446) and NSF (IIA-1301765). \n\nAuthor Contributions: N.N., E.C., Z.D., D.T., S.L.B., F.J., A.M.W., P.P., A.T., R.S., M.F.R., A.S., T.M., S.S., and M.M. performed and analyzed experiments involving biochemical, mitochondrial bioenergetics, and molecular and cellular experiments. N.N. and M.M. developed the MiST assay. N.N. and E.C. performed MiST imaging and analysis. Z.D. and D.T. performed immunoprecipitation and western blot analysis. A.K. and G.G. performed MiST imaging and analysis in primary neurons. J.H. and B.P. performed MiST imaging in primary cardiomyocytes. P.B.S. performed Miro EF structural analysis. J.C. performed EM imaging of ER-mitochondrial contact sites. S.M., P.M., and D.C.C. generated WT and MFF/Fis1 DKO MEFs. H.S. generated WT and Drp1 KO MEFs. W.J.C. generated WT and VDAC1/3 DKO MEFs. N.N., E.C., and S.R. cloned and generated plasmid constructs. N.N., E.C., and M.M. conceived, designed, analyzed, and interpreted experimental data. N.N., E.C., S.L.B., and M.M. wrote the manuscript with contributions from G.G., H.S., D.L.G., P.M., and D.C.C. All authors commented on the manuscript. \n\nThe authors declare no competing interests.\n\nPublished - 1-s2.0-S2211124718304741-main.pdf
Accepted Version - nihms965664.pdf
Supplemental Material - mmc1.pdf
Supplemental Material - mmc2.mp4
Supplemental Material - mmc3.mp4
Supplemental Material - mmc4.mp4
Supplemental Material - mmc5.mp4
Supplemental Material - mmc6.mp4
", "abstract": "Mitochondria shape cytosolic calcium ([Ca^(2+)]_c) transients and utilize the mitochondrial Ca_2^+ ([Ca^(2+)]_m) in exchange for bioenergetics output. Conversely, dysregulated [Ca^(2+)]_c causes [Ca^(2+)]_m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca^(2+) uptake exhibited elevated [Ca^(2+)]_c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca^(2+)-induced shape change that is distinct from mitochondrial fission and swelling. [Ca^(2+)]_c elevation, but not MCU-mediated Ca^(2+) uptake, appears to be essential for the process we term mitochondrial shape transition (MiST). MiST is mediated by the mitochondrial protein Miro1 through its EF-hand domain 1 in multiple cell types. Moreover, Ca^(2+)-dependent disruption of Miro1/KIF5B/tubulin complex is determined by Miro1 EF1 domain. Functionally, Miro1-dependent MiST is essential for autophagy/mitophagy that is attenuated in Miro1 EF1 mutants. Thus, Miro1 is a cytosolic Ca^(2+) sensor that decodes metazoan Ca^(2+) signals as MiST.", "date": "2018-04-24", "date_type": "published", "publication": "Cell Reports", "volume": "23", "number": "4", "publisher": "Cell Press", "pagerange": "1005-1019", "id_number": "CaltechAUTHORS:20180425-144714424", "issn": "2211-1247", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180425-144714424", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01GM109882" }, { "agency": "NIH", "grant_number": "R01HL086699" }, { "agency": "NIH", "grant_number": "R01HL119306" }, { "agency": "NIH", "grant_number": "1S10RR027327" }, { "agency": "NIH", "grant_number": "R01 NS095471" }, { "agency": "American Heart Association", "grant_number": "17PRE33660720" }, { "agency": "American Heart Association", "grant_number": "17POST33660251" }, { "agency": "NIH", "grant_number": "1K99HL138268-01" }, { "agency": "China Scholarship Council", "grant_number": "201403170252" }, { "agency": "Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico (FONDECYT)", "grant_number": "3140458" }, { "agency": "NIH", "grant_number": "P20 GM103446" }, { "agency": "NSF", "grant_number": "IIA-1301765" } ] }, "doi": "10.1016/j.celrep.2018.03.098", "pmcid": "PMC5973819", "primary_object": { "basename": "1-s2.0-S2211124718304741-main.pdf", "url": "https://authors.library.caltech.edu/records/4c2bz-2se92/files/1-s2.0-S2211124718304741-main.pdf" }, "related_objects": [ { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/4c2bz-2se92/files/mmc1.pdf" }, { "basename": "mmc2.mp4", "url": "https://authors.library.caltech.edu/records/4c2bz-2se92/files/mmc2.mp4" }, { "basename": "mmc3.mp4", "url": "https://authors.library.caltech.edu/records/4c2bz-2se92/files/mmc3.mp4" }, { "basename": "mmc4.mp4", "url": "https://authors.library.caltech.edu/records/4c2bz-2se92/files/mmc4.mp4" }, { "basename": "mmc5.mp4", "url": "https://authors.library.caltech.edu/records/4c2bz-2se92/files/mmc5.mp4" }, { "basename": "mmc6.mp4", "url": "https://authors.library.caltech.edu/records/4c2bz-2se92/files/mmc6.mp4" }, { "basename": "nihms965664.pdf", "url": "https://authors.library.caltech.edu/records/4c2bz-2se92/files/nihms965664.pdf" } ], "resource_type": "article", "pub_year": "2018", "author_list": "Nemani, Neeharika; Carvalho, Edmund; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/ae49z-48g84", "eprint_id": 85746, "eprint_status": "archive", "datestamp": "2023-08-19 08:02:13", "lastmod": "2023-10-18 18:44:34", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial fusion and fission in health and disease", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2017 Elsevier Inc. \n\nAvailable online 7 February 2018.", "abstract": "[no abstract]", "date": "2018-03", "date_type": "published", "publication": "Molecular Genetics and Metabolism", "volume": "123", "number": "3", "publisher": "Elsevier", "pagerange": "196", "id_number": "CaltechAUTHORS:20180411-111634786", "issn": "1096-7192", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180411-111634786", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.ymgme.2017.12.430", "resource_type": "article", "pub_year": "2018", "author_list": "Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/zrkbm-c0028", "eprint_id": 83746, "eprint_status": "archive", "datestamp": "2023-08-19 05:50:32", "lastmod": "2023-10-17 23:28:30", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Molecular Analysis Of Mitochondrial Dynamics", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2017 Published by Elsevier Inc. \n\nAvailable online 20 November 2017.", "abstract": "The dynamics properties of mitochondria control their function. I will update our efforts to understand the molecular mechanisms of mitochondrial dynamics and their physiological functions. I will also discuss our use of somatic cell genetics to identify genes involved in mitochondrial function. This includes our attempt to understand why cancer cells are dependent on glucose metabolism. In such a screen, we identified the xCT antiporter, which plays an antioxidant role by exporting glutamate for cystine. Disruption of the xCT antiporter greatly improves cell viability after glucose withdrawal, because conservation of glutamate enables cells to maintain mitochondrial respiration. In some breast cancer cells, xCT antiporter expression is upregulated through the antioxidant transcription factor Nrf2 and contributes to their requirement for glucose as a carbon source.", "date": "2017-11", "date_type": "published", "publication": "Free Radical Biology and Medicine", "volume": "112", "number": "S1", "publisher": "Elsevier", "pagerange": "17", "id_number": "CaltechAUTHORS:20171208-073351141", "issn": "0891-5849", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20171208-073351141", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.freeradbiomed.2017.10.371", "resource_type": "article", "pub_year": "2017", "author_list": "Chan, David" }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/2qb8a-fje66", "eprint_id": 81891, "eprint_status": "archive", "datestamp": "2023-08-19 04:54:39", "lastmod": "2023-10-17 21:54:15", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-J", "name": { "family": "Li", "given": "J." } }, { "id": "Lancaster-E", "name": { "family": "Lancaster", "given": "E." } }, { "id": "Yousaf-A", "name": { "family": "Yousaf", "given": "A." } }, { "id": "Hanania-T", "name": { "family": "Hanania", "given": "T." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "D." }, "orcid": "0000-0002-0191-2154" }, { "id": "Lunn-J-S", "name": { "family": "Lunn", "given": "J. S." } }, { "id": "Kidd-G", "name": { "family": "Kidd", "given": "G." } }, { "id": "Svaren-J", "name": { "family": "Svaren", "given": "J." } }, { "id": "Scheideler-M", "name": { "family": "Scheideler", "given": "M." } }, { "id": "Scherer-S-S", "name": { "family": "Scherer", "given": "S. S." } } ] }, "title": "A Rat Model of CMT2A Develops a Progressive Neuropathy", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2017 Peripheral Nerve Society. \n\nIssue online: 5 September 2017; Version of record online: 22 June 2017; Accepted manuscript online: 14 June 2017.", "abstract": "[No abstract]", "date": "2017-09", "date_type": "published", "publication": "Journal of the Peripheral Nervous System", "volume": "22", "number": "3", "publisher": "Wiley", "pagerange": "331", "id_number": "CaltechAUTHORS:20170928-074802946", "issn": "1085-9489", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170928-074802946", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1111/jns.12225", "resource_type": "article", "pub_year": "2017", "author_list": "Li, J.; Lancaster, E.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/n8gjs-92n87", "eprint_id": 78601, "eprint_status": "archive", "datestamp": "2023-08-21 21:24:43", "lastmod": "2023-10-26 00:13:19", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells", "ispublished": "pub", "full_text_status": "public", "keywords": "mitochondria; mitochondrial dynamics; stem cells; induced pluripotential stem cells; cancer; metabolism", "note": "\u00a9 2017 Elsevier Inc. \n\nAvailable online 22 June 2017.\n\nAccepted Version - nihms885679.pdf
", "abstract": "Cancer and stem cells appear to share a common metabolic profile that is characterized by high utilization of glucose through aerobic glycolysis. In the presence of sufficient nutrients, this metabolic strategy provides sufficient cellular ATP while additionally providing important metabolites necessary for the biosynthetic demands of continuous cell proliferation. Recent studies indicate that this metabolic profile is dependent on genes that regulate the fusion and fission of mitochondria. High levels of mitochondrial fission activity are associated with high proliferation and invasiveness in some cancer cells and with self-renewal and resistance to differentiation in some stem cells. These observations reveal new ways in which mitochondria regulate cell physiology, through their effects on metabolism and cell signaling.", "date": "2017-07-05", "date_type": "published", "publication": "Cell Metabolism", "volume": "26", "number": "1", "publisher": "Cell Press", "pagerange": "39-48", "id_number": "CaltechAUTHORS:20170627-094323553", "issn": "1550-4131", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170627-094323553", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.cmet.2017.05.016", "pmcid": "PMC5539982", "primary_object": { "basename": "nihms885679.pdf", "url": "https://authors.library.caltech.edu/records/n8gjs-92n87/files/nihms885679.pdf" }, "resource_type": "article", "pub_year": "2017", "author_list": "Chen, Hsiuchen and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/4ry4h-cdw66", "eprint_id": 78366, "eprint_status": "archive", "datestamp": "2023-08-19 03:52:21", "lastmod": "2023-10-26 00:02:41", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Liu-Raymond", "name": { "family": "Liu", "given": "Raymond" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "OPA1 and cardiolipin team up for mitochondrial fusion", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2017 Macmillan Publishers Limited, part of Springer Nature. \n\nPublished online 19 June 2017. \n\nThe authors declare no competing financial interests.\n\nAccepted Version - nihms929351.pdf
", "abstract": "Fusion between the inner membranes of two mitochondria requires the GTPase optic atrophy 1 (OPA1), but the molecular mechanism is poorly understood. A study now shows that fusion of two liposomes can be performed by OPA1 tethered to just one liposome, through an interaction with the phospholipid cardiolipin on the opposing liposome.", "date": "2017-07", "date_type": "published", "publication": "Nature Cell Biology", "volume": "19", "number": "7", "publisher": "Nature Publishing Group", "pagerange": "760-762", "id_number": "CaltechAUTHORS:20170620-091459936", "issn": "1465-7392", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170620-091459936", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1038/ncb3565", "pmcid": "PMC5757513", "primary_object": { "basename": "nihms929351.pdf", "url": "https://authors.library.caltech.edu/records/4ry4h-cdw66/files/nihms929351.pdf" }, "resource_type": "article", "pub_year": "2017", "author_list": "Liu, Raymond and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/2p5r1-4rq49", "eprint_id": 78605, "eprint_status": "archive", "datestamp": "2023-08-21 21:16:17", "lastmod": "2023-10-26 00:13:35", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Del-Dotto-V", "name": { "family": "Del Dotto", "given": "Valentina" } }, { "id": "Mishra-P", "name": { "family": "Mishra", "given": "Prashant" } }, { "id": "Vidoni-S", "name": { "family": "Vidoni", "given": "Sara" } }, { "id": "Fogazza-M", "name": { "family": "Fogazza", "given": "Mario" } }, { "id": "Maresca-A", "name": { "family": "Maresca", "given": "Alessandra" }, "orcid": "0000-0002-8959-8832" }, { "id": "Caporali-L", "name": { "family": "Caporali", "given": "Leonardo" } }, { "id": "McCaffery-J-M", "name": { "family": "McCaffery", "given": "J. Michael" } }, { "id": "Cappelletti-M", "name": { "family": "Cappelletti", "given": "Martina" } }, { "id": "Baruffini-E", "name": { "family": "Baruffini", "given": "Enrico" } }, { "id": "Lenaers-G", "name": { "family": "Lenaers", "given": "Guy" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" }, { "id": "Rugolo-M", "name": { "family": "Rugolo", "given": "Michela" } }, { "id": "Carelli-V", "name": { "family": "Carelli", "given": "Valerio" } }, { "id": "Zanna-C", "name": { "family": "Zanna", "given": "Claudia" } } ] }, "title": "OPA1 Isoforms in the Hierarchical Organization of Mitochondrial Functions", "ispublished": "pub", "full_text_status": "public", "keywords": "dominant optic atrophy; mitochondrial network dynamics; mtDNA; OPA1 isoforms; OPA1 long-short form balance", "note": "\u00a9 2017 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). \n\nPublished: June 20, 2017. \n\nThis research was supported by grants from Ministero della Istruzione Universit\u00e0 e Ricerca, MIUR (FIR2013 grant J38C13001770001 to C.Z. and PRIN grant 20107Z8XBW to M.R.), the NIH (grant GM110039 to D.C.), and E-Rare project 2009-ERMION to V.C., M.R., and G.L. V.D.D. was the recipient of a Marco Polo fellowship, University of Bologna.\n\nPublished - PIIS2211124717307465.pdf
Supplemental Material - mmc1.pdf
", "abstract": "OPA1 is a GTPase that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In humans, eight isoforms are expressed as combinations of long and short forms, but it is unclear whether OPA1 functions are associated with specific isoforms and/or domains. To address this, we expressed each of the eight isoforms or different constructs of isoform 1 in Opa1\u2212/\u2212 MEFs. We observed that any isoform could restore cristae structure, mtDNA abundance, and energetic efficiency independently of mitochondrial network morphology. Long forms supported mitochondrial fusion; short forms were better able to restore energetic efficiency. The complete rescue of mitochondrial network morphology required a balance of long and short forms of at least two isoforms, as shown by combinatorial isoform silencing and co-expression experiments. Thus, multiple OPA1 isoforms are required for mitochondrial dynamics, while any single isoform can support all other functions. These findings will be useful in designing gene therapies for patients with OPA1 haploinsufficiency.", "date": "2017-06-20", "date_type": "published", "publication": "Cell Reports", "volume": "19", "number": "12", "publisher": "Elsevier", "pagerange": "2557-2571", "id_number": "CaltechAUTHORS:20170627-102931021", "issn": "2211-1247", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170627-102931021", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Ministero della Istruzione Universit\u00e0 e Ricerca (MIUR)", "grant_number": "J38C13001770001" }, { "agency": "Ministero della Istruzione Universit\u00e0 e Ricerca (MIUR)", "grant_number": "20107Z8XBW" }, { "agency": "NIH", "grant_number": "GM110039" }, { "agency": "E-Rare Project", "grant_number": "2009-ERMION" }, { "agency": "University of Bologna" } ] }, "doi": "10.1016/j.celrep.2017.05.073", "primary_object": { "basename": "PIIS2211124717307465.pdf", "url": "https://authors.library.caltech.edu/records/2p5r1-4rq49/files/PIIS2211124717307465.pdf" }, "related_objects": [ { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/2p5r1-4rq49/files/mmc1.pdf" } ], "resource_type": "article", "pub_year": "2017", "author_list": "Del Dotto, Valentina; Mishra, Prashant; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/1mjj1-92k65", "eprint_id": 76847, "eprint_status": "archive", "datestamp": "2023-08-19 02:42:29", "lastmod": "2023-10-25 16:55:12", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Shin-Chun-Shik", "name": { "family": "Shin", "given": "Chun-Shik" }, "orcid": "0000-0002-1382-9876" }, { "id": "Mishra-Prashant", "name": { "family": "Mishra", "given": "Prashant" } }, { "id": "Watrous-Jeramie-D", "name": { "family": "Watrous", "given": "Jeramie D." } }, { "id": "Carelli-Valerio", "name": { "family": "Carelli", "given": "Valerio" } }, { "id": "D'Aurelio-Marilena", "name": { "family": "D'Aurelio", "given": "Marilena" } }, { "id": "Jain-Mohit", "name": { "family": "Jain", "given": "Mohit" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 The Author(s) 2017. \n\nReceived: 30 August 2016. Accepted: 24 February 2017. Published online: 21 April 2017. \n\nHap1 cells were generously provided by Thijn Brummelkamp (Netherlands Cancer Institute), and SK-BR-3 and MDA-MB-231 cells were provided by Raymond Deshaies (Caltech). We also thank Hsiuchen Chen for insightful discussions and comments. This work was supported by a grant from the National Institute of Health (GM110039) to D.C.C., and grants from the Mary Kay Foundation, the V Foundation for Cancer Research and the Sidney Kimmel Foundation to M.J. \n\nAuthor Contributions: C.-S.S. and D.C.C. conceived the overall project, with contributions from P.M. C.-S.S. performed the majority of the experimental work. P.M. performed some experiments with cybrid cell lines, which were provided by V.C. and M.D'A. J.D.W. and M.J. performed and analysed the mass spectrometry studies. C.-S.S. and D.C.C. wrote the paper, and all authors provided input. \n\nThe authors declare no competing financial interests.\n\nPublished - ncomms15074.pdf
Supplemental Material - ncomms15074-s1.pdf
Supplemental Material - ncomms15074-s2.pdf
", "abstract": "As noted by Warburg, many cancer cells depend on the consumption of glucose. We performed a genetic screen to identify factors responsible for glucose addiction and recovered the two subunits of the xCT antiporter (system xc\u2212), which plays an antioxidant role by exporting glutamate for cystine. Disruption of the xCT antiporter greatly improves cell viability after glucose withdrawal, because conservation of glutamate enables cells to maintain mitochondrial respiration. In some breast cancer cells, xCT antiporter expression is upregulated through the antioxidant transcription factor Nrf2 and contributes to their requirement for glucose as a carbon source. In cells carrying patient-derived mitochondrial DNA mutations, the xCT antiporter is upregulated and its inhibition improves mitochondrial function and cell viability. Therefore, although upregulation of the xCT antiporter promotes antioxidant defence, it antagonizes glutamine metabolism and restricts nutrient flexibility. In cells with mitochondrial dysfunction, the potential utility of xCT antiporter inhibition should be further tested.", "date": "2017-04-21", "date_type": "published", "publication": "Nature Communications", "volume": "8", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 15074", "id_number": "CaltechAUTHORS:20170424-103533161", "issn": "2041-1723", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170424-103533161", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM110039" }, { "agency": "V Foundation for Cancer Research" }, { "agency": "Sidney Kimmel Foundation" } ] }, "doi": "10.1038/ncomms15074", "pmcid": "PMC5413954", "primary_object": { "basename": "ncomms15074-s1.pdf", "url": "https://authors.library.caltech.edu/records/1mjj1-92k65/files/ncomms15074-s1.pdf" }, "related_objects": [ { "basename": "ncomms15074-s2.pdf", "url": "https://authors.library.caltech.edu/records/1mjj1-92k65/files/ncomms15074-s2.pdf" }, { "basename": "ncomms15074.pdf", "url": "https://authors.library.caltech.edu/records/1mjj1-92k65/files/ncomms15074.pdf" } ], "resource_type": "article", "pub_year": "2017", "author_list": "Shin, Chun-Shik; Mishra, Prashant; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/xs8yc-7h141", "eprint_id": 75413, "eprint_status": "archive", "datestamp": "2023-08-19 02:07:48", "lastmod": "2023-10-25 15:01:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zhang-Ting", "name": { "family": "Zhang", "given": "Ting" } }, { "id": "Mishra-P", "name": { "family": "Mishra", "given": "Prashant" } }, { "id": "Hay-B-A", "name": { "family": "Hay", "given": "Bruce A." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" }, { "id": "Guo-Ming", "name": { "family": "Guo", "given": "Ming" } } ] }, "title": "Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2017 Zhang et al. This article is distributed under the\nterms of the Creative Commons Attribution License, which\npermits unrestricted use and redistribution provided that the original author and source are credited. \n\nReceived: 15 May 2016; Accepted: 13 February 2017; Published: 21 March 2017. \n\nWe are grateful to the support of the Natalie R and Eugene S Jones Fund in Aging and Neurode-generative Disease Research. We would like to thank Hansong Deng for first noting the suppression of PINK1 mutant phenotype by VCP overexpression, Dr. Tzu Kang Sang from the National Tsing Hua University, Taiwan, for the VCP disease mutants allele flies, Dr. Hugo Bellen from the Baylor College of Medicine for the kind gift of pCasper-Mfn-HA flies, Dr. CK Yao from Academia Sinica, Taipei, for pCasper-Mfn-eGFP construct and Dr. Frank A Laski for the microtome usage. \n\nAuthor contributions: TZ, PM, BAH, Conceptualization, Methodology, Writing\u2014original draft, Writing\u2014review and editing; DC, Conceptualization, Supervision, Data curation, Formal analysis, Writing\u2014original draft, Writing\u2014review and editing; MG, Conceptualization, Supervision, Funding acquisition, Data curation, Formal analysis, Methodology, Writing\u2014original draft, Writing\u2014review and editing. \n\nThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. \n\nThe authors declare that no competing interests exist.\n\nPublished - e17834-download.pdf
", "abstract": "Missense mutations of valosin-containing protein (VCP) cause an autosomal dominant disease known as inclusion body myopathy, Paget disease with frontotemporal dementia (IBMPFD) and other neurodegenerative disorders. The pathological mechanism of IBMPFD is not clear and there is no treatment. We show that endogenous VCP negatively regulates Mitofusin, which is required for outer mitochondrial membrane fusion. Because 90% of IBMPFD patients have myopathy, we generated an in vivo IBMPFD model in adult Drosophila muscle, which recapitulates disease pathologies. We show that common VCP disease mutants act as hyperactive alleles with respect to regulation of Mitofusin. Importantly, VCP inhibitors suppress mitochondrial defects, muscle tissue damage and cell death associated with IBMPFD models in Drosophila. These inhibitors also suppress mitochondrial fusion and respiratory defects in IBMPFD patient fibroblasts. These results suggest that VCP disease mutants cause IBMPFD through a gain-of-function mechanism, and that VCP inhibitors have therapeutic value.", "date": "2017-03-21", "date_type": "published", "publication": "eLife", "volume": "6", "publisher": "eLife Sciences Publications", "pagerange": "Art. No. e17834", "id_number": "CaltechAUTHORS:20170327-104810282", "issn": "2050-084X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170327-104810282", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Ellison Medical Foundation" }, { "agency": "McKnight Endowment Fund for Neuroscience" }, { "agency": "Glenn Family Foundation" }, { "agency": "NIH" }, { "agency": "Natalie R. and Eugene S. Jones Fund in Aging and Neurodegenerative Disease Research" } ] }, "collection": "CaltechAUTHORS", "doi": "10.7554/eLife.17834", "pmcid": "PMC5360448", "primary_object": { "basename": "e17834-download.pdf", "url": "https://authors.library.caltech.edu/records/xs8yc-7h141/files/e17834-download.pdf" }, "resource_type": "article", "pub_year": "2017", "author_list": "Zhang, Ting; Mishra, Prashant; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/jrezm-9q397", "eprint_id": 72921, "eprint_status": "archive", "datestamp": "2023-08-19 01:33:35", "lastmod": "2023-10-23 23:24:17", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Cao-Yu-Lu", "name": { "family": "Cao", "given": "Yu-Lu" }, "orcid": "0000-0002-5239-1184" }, { "id": "Meng-Shuxia", "name": { "family": "Meng", "given": "Shuxia" } }, { "id": "Chen-Yang", "name": { "family": "Chen", "given": "Yang" }, "orcid": "0000-0002-8964-0084" }, { "id": "Feng-Jian-Xiong", "name": { "family": "Feng", "given": "Jian-Xiong" } }, { "id": "Gu-Dong-Dong", "name": { "family": "Gu", "given": "Dong-Dong" } }, { "id": "Yu-Bing", "name": { "family": "Yu", "given": "Bing" } }, { "id": "Li-Yu-Jie", "name": { "family": "Li", "given": "Yu-Jie" }, "orcid": "0000-0002-8425-386X" }, { "id": "Yang-Jin-Yu", "name": { "family": "Yang", "given": "Jin-Yu" } }, { "id": "Liao-Shuang", "name": { "family": "Liao", "given": "Shuang" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Gao-Song", "name": { "family": "Gao", "given": "Song" }, "orcid": "0000-0001-7427-6681" } ] }, "title": "MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2017 Macmillan Publishers Limited. \n\nReceived 27 July 2016; accepted 3 January 2017. Published online 23 January 2017. \n\nWe thank the staff at beamline BL17U1 of SSRF for the help with the collection of diffraction data, W.-L. Huang and H.-Y. Wang for technical assistance, J. Hu and X. Guo for advice on liposome tethering assay, and O. Daumke for comments on the manuscript. This work was supported by grants of National Basic Research Program of China (2013CB910500), National Natural Science Foundation of China (31200553), Natural Science Foundation of Guangdong Province (2014TQ01R584 and 2014A030312015), New Century Excellent Talents in University (NCET-12-0567) and the Recruitment Program of Global Youth Experts to S.G., and the National Institutes of Health (GM110039 and GM119388) to D.C.C. \n\nData availability: The X-ray crystallographic coordinates and structure factor files for MFN1IM structures have been deposited in the Protein Data Bank (PDB) under the following accession numbers: 5GO4 (apo MFNIMB), 5GOF (GTP-bound MFN1IMC(T109A)), 5GOM (transition-like state MFN1IMC), and 5GOE (GDP-bound MFN1IMC(T109A)). All other data generated or analysed during this study are included in this published article, and are available from the corresponding author upon reasonable request. \n\nAuthor Contributions: S.G. and D.C.C. conceived the project. Y.-L.C. made the constructs, purified proteins, and performed crystallographic and biochemical experiments. S.M. carried out mitochondrial elongation assays. Y.C. performed ITC measurements and helped with collection of X-ray diffraction data. J.-X.F., B.Y. and Y.-J.L. performed cloning and purification for some of the MFN1IM mutants. D.-D.G. performed some of the SEC-RALS experiments, D.-D.G., J.-Y.Y. and S.L. helped with crystallization experiments. Y.-L.C., S.L. and S.G. solved the structures. Y.-L.C., D.C.C. and S.G. wrote the paper. \n\nThe authors declare no competing financial interests. \n\nReviewer Information: Nature thanks M. Ford and the other anonymous reviewer(s) for their contribution to the peer review of this work.\n\nAccepted Version - nihms840668.pdf
Supplemental Material - nature21077-sf1.jpg
Supplemental Material - nature21077-sf2.jpg
Supplemental Material - nature21077-sf3.jpg
Supplemental Material - nature21077-sf4.jpg
Supplemental Material - nature21077-sf5.jpg
Supplemental Material - nature21077-sf6.jpg
Supplemental Material - nature21077-sf7.jpg
Supplemental Material - nature21077-sf8.jpg
Supplemental Material - nature21077-sf9.jpg
Supplemental Material - nature21077-st1.jpg
", "abstract": "Mitochondria are double-membraned organelles with variable shapes influenced by metabolic conditions, developmental stage, and environmental stimuli. Their dynamic morphology is a result of regulated and balanced fusion and fission processes. Fusion is crucial for the health and physiological functions of mitochondria, including complementation of damaged mitochondrial DNAs and the maintenance of membrane potential. Mitofusins are dynamin-related GTPases that are essential for mitochondrial fusion. They are embedded in the mitochondrial outer membrane and thought to fuse adjacent mitochondria via combined oligomerization and GTP hydrolysis. However, the molecular mechanisms of this process remain unknown. Here we present crystal structures of engineered human MFN1 containing the GTPase domain and a helical domain during different stages of GTP hydrolysis. The helical domain is composed of elements from widely dispersed sequence regions of MFN1 and resembles the 'neck' of the bacterial dynamin-like protein. The structures reveal unique features of its catalytic machinery and explain how GTP binding induces conformational changes to promote GTPase domain dimerization in the transition state. Disruption of GTPase domain dimerization abolishes the fusogenic activity of MFN1. Moreover, a conserved aspartate residue trigger was found to affect mitochondrial elongation in MFN1, probably through a GTP-loading-dependent domain rearrangement. Thus, we propose a mechanistic model for MFN1-mediated mitochondrial tethering, and our results shed light on the molecular basis of mitochondrial fusion and mitofusin-related human neuromuscular disorders.", "date": "2017-02-16", "date_type": "published", "publication": "Nature", "volume": "542", "number": "7641", "publisher": "Nature Publishing Group", "pagerange": "372-376", "id_number": "CaltechAUTHORS:20161216-173743897", "issn": "0028-0836", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161216-173743897", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Basic Research Program of China", "grant_number": "2013CB910500" }, { "agency": "National Natural Science Foundation of China", "grant_number": "31200553" }, { "agency": "Natural Science Foundation of Guangdong Province", "grant_number": "2014TQ01R584" }, { "agency": "Natural Science Foundation of Guangdong Province", "grant_number": "2014A030312015" }, { "agency": "New Century Excellent Talents in University", "grant_number": "NCET-12-0567" }, { "agency": "Recruitment Program of Global Youth Experts" }, { "agency": "NIH", "grant_number": "GM110039" }, { "agency": "NIH", "grant_number": "GM119388" } ] }, "collection": "CaltechAUTHORS", "doi": "10.1038/nature21077", "pmcid": "PMC5319402", "primary_object": { "basename": "nature21077-sf1.jpg", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nature21077-sf1.jpg" }, "related_objects": [ { "basename": "nature21077-sf8.jpg", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nature21077-sf8.jpg" }, { "basename": "nihms840668.pdf", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nihms840668.pdf" }, { "basename": "nature21077-sf3.jpg", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nature21077-sf3.jpg" }, { "basename": "nature21077-sf4.jpg", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nature21077-sf4.jpg" }, { "basename": "nature21077-sf9.jpg", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nature21077-sf9.jpg" }, { "basename": "nature21077-sf5.jpg", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nature21077-sf5.jpg" }, { "basename": "nature21077-sf7.jpg", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nature21077-sf7.jpg" }, { "basename": "nature21077-sf6.jpg", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nature21077-sf6.jpg" }, { "basename": "nature21077-st1.jpg", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nature21077-st1.jpg" }, { "basename": "nature21077-sf2.jpg", "url": "https://authors.library.caltech.edu/records/jrezm-9q397/files/nature21077-sf2.jpg" } ], "resource_type": "article", "pub_year": "2017", "author_list": "Cao, Yu-Lu; Meng, Shuxia; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/nv7vt-c6p81", "eprint_id": 78515, "eprint_status": "archive", "datestamp": "2023-08-19 01:24:53", "lastmod": "2023-10-26 00:09:56", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Control of Mitochondrial Function by Fusion and Fission", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2017 Elsevier B.V. \n\nAvailable online 3 February 2017. \n\n\nMeeting Abstract: 886-Symp.", "abstract": "Several neurodegenerative diseases are associated with defects in mitochondrial fusion or fission, which are opposing processes that regulate mitochondrial function. This observation raises the issue of whether a defect in one process can be alleviated by simultaneously reducing the opposing process. We used mouse models to address this issue. Mff is a mitochondrial outer membrane protein important for mitochondrial fission. We generated Mff mutant mice and found that they die at 13 weeks due to heart failure caused by dilated cardiomyopathy. Mff cardiac tissue shows reduced mitochondrial density, reduced respiratory chain activity, and increased mitophagy. Mfn1 deficient mice die shortly after birth. However, mice with loss of both Mff and Mfn1 have normal heart function, lifespan and respiratory chain function. The reciprocal rescue with both mutations indicate that retuning mitochondrial dynamics can restore tissue integrity and mitochondrial physiology at the whole organ level.", "date": "2017-02-03", "date_type": "published", "publication": "Biophysical Journal", "volume": "112", "number": "3, Supp. 1", "publisher": "Biophysical Society", "pagerange": "179a", "id_number": "CaltechAUTHORS:20170623-104426059", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170623-104426059", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "collection": "CaltechAUTHORS", "doi": "10.1016/j.bpj.2016.11.994", "resource_type": "article", "pub_year": "2017", "author_list": "Chen, Hsiuchen and Chan, David" }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/82tz2-gw313", "eprint_id": 75596, "eprint_status": "archive", "datestamp": "2023-08-19 00:19:35", "lastmod": "2023-10-25 15:10:07", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Huang-R-E", "name": { "family": "Huang", "given": "R. E." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "D. C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Investigating the roles of Mulan and Fis1 in Mitophagy", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 American Society for Cell Biology.\n\nPublished - Huang_2016pP2161.pdf
", "abstract": "Mitochondria are highly dynamic organelles that respond to physiological stimuli by moving, fusing together, and dividing. Because of this high degree of interaction, it is important for cells to sequester and degrade damaged mitochondria in order to maintain the health of the mitochondrial reticulum. Though mitochondrial autophagy, or mitophagy, has traditionally been thought to require \na ubiquitin ligase called Parkin, recent studies have found stress conditions that promote Parkin\u2010independent mitophagy. These conditions may instead depend on Mulan, a ubiquitin ligase that works in parallel to Parkin in ubiquitinating mitofusin proteins, and/or Fis1, a protein that has been implicated in autophagosome recruitment during mammalian mitophagy. We investigated mitophagy \nrates in mouse embryonic fibroblasts under two stress conditions: the addition of the iron chelator deferiprone and post\u2010confluent cell growth. Our results suggest that deferiprone\u2010induced mitophagy is dependent on Parkin, Mulan, and Fis1, while mitophagy induced in post\u2010confluent conditions is independent of all three proteins. Both pathways rely on Atg3, a general autophagy factor. These data suggest that, in the latter condition, mitochondria are being degraded either as a by\u2010product of increased general autophagy or through a novel mitophagy pathway. Additionally, Fis1\u2010/\u2010 cells in deferiprone conditions show incomplete inactivation of a pH\u2010sensitive mitophagy marker, which may suggest a role for Fis1 in acidifying the lysosome where mitophagy is completed.", "date": "2016-12", "date_type": "published", "publication": "Molecular Biology of the Cell", "volume": "27", "publisher": "American Society for Cell Biology", "pagerange": "Art. No. P2161", "id_number": "CaltechAUTHORS:20170331-133654121", "issn": "1059-1524", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170331-133654121", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "primary_object": { "basename": "Huang_2016pP2161.pdf", "url": "https://authors.library.caltech.edu/records/82tz2-gw313/files/Huang_2016pP2161.pdf" }, "resource_type": "article", "pub_year": "2016", "author_list": "Huang, R. E. and Chan, D. C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/xv89b-ahq03", "eprint_id": 72195, "eprint_status": "archive", "datestamp": "2023-08-19 00:05:19", "lastmod": "2023-10-23 18:02:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rojansky-R", "name": { "family": "Rojansky", "given": "Rebecca" } }, { "id": "Cha-Moon-Yong", "name": { "family": "Cha", "given": "Moon-Yong" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016, Rojansky et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited. \n\nReceived May 17, 2016. Accepted November 14, 2016. Published November 17, 2016. \n\n\nWe are grateful to Shirley Pease (Director, Transgenic Core at Caltech) for training and advice on embryo injection. We thank Katherine Kim for preliminary work with MUL1 knockdown experiments, Kurt Reichermeier for advice on the ubiquitin assay, Ruohan Wang for technical assistance with p62 overexpression, and Hsiuchen Chen for advice on animal work. RR is supported by an NIH NIGMS training grant (GM08042) and the UCLA Medical Scientist Training Program.\n\nFunding: \nNational Institute of General Medical Sciences - GM08042. National Institutes of Health - GM119388, GM083121. \n\nThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. \n\nAuthor Contributions:\nRR, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article; M-YC, Acquisition of data, Analysis and interpretation of data; DCC, Conception and design, Analysis and interpretation of data, Drafting or revising the article\n\nPublished - e17896-download.pdf
Supplemental Material - elife-17896-supp-v1.zip
", "abstract": "A defining feature of mitochondria is their maternal mode of inheritance. However, little is understood about the cellular mechanism through which paternal mitochondria, delivered from sperm, are eliminated from early mammalian embryos. Autophagy has been implicated in nematodes, but whether this mechanism is conserved in mammals has been disputed. Here, we show that cultured mouse fibroblasts and pre-implantation embryos use a common pathway for elimination of mitochondria. Both situations utilize mitophagy, in which mitochondria are sequestered by autophagosomes and delivered to lysosomes for degradation. The E3 ubiquitin ligases PARKIN and MUL1 play redundant roles in elimination of paternal mitochondria. The process is associated with depolarization of paternal mitochondria and additionally requires the mitochondrial outer membrane protein FIS1, the autophagy adaptor P62, and PINK1 kinase. Our results indicate that strict maternal transmission of mitochondria relies on mitophagy and uncover a collaboration between MUL1 and PARKIN in this process.", "date": "2016-11-17", "date_type": "published", "publication": "eLife", "volume": "5", "publisher": "eLife Sciences Publications", "pagerange": "Art. No. e17896", "id_number": "CaltechAUTHORS:20161121-101729796", "issn": "2050-084X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161121-101729796", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM08042" }, { "agency": "UCLA Medical Scientist Training Program" }, { "agency": "NIH", "grant_number": "GM119388" }, { "agency": "NIH", "grant_number": "GM083121" } ] }, "collection": "CaltechAUTHORS", "doi": "10.7554/eLife.17896", "pmcid": "PMC5127638", "primary_object": { "basename": "e17896-download.pdf", "url": "https://authors.library.caltech.edu/records/xv89b-ahq03/files/e17896-download.pdf" }, "related_objects": [ { "basename": "elife-17896-supp-v1.zip", "url": "https://authors.library.caltech.edu/records/xv89b-ahq03/files/elife-17896-supp-v1.zip" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Rojansky, Rebecca; Cha, Moon-Yong; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/fwzxw-xat51", "eprint_id": 73131, "eprint_status": "archive", "datestamp": "2023-08-20 14:22:30", "lastmod": "2023-10-24 15:04:00", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Mishra-P", "name": { "family": "Mishra", "given": "Prashant" } }, { "id": "Varuzhanyan-G", "name": { "family": "Varuzhanyan", "given": "Grigor" }, "orcid": "0000-0001-6165-0857" }, { "id": "Pham-Anh-H", "name": { "family": "Pham", "given": "Anh H." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Regulation of mitochondrial compartmentalization in skeletal muscle", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 Elsevier B.V. and Mitochondria Research Society.", "abstract": "[no abstract]", "date": "2016-11", "date_type": "published", "publication": "Mitochondrion", "volume": "31", "publisher": "Elsevier", "pagerange": "96", "id_number": "CaltechAUTHORS:20161222-092658901", "issn": "1567-7249", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161222-092658901", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.mito.2016.08.010", "resource_type": "article", "pub_year": "2016", "author_list": "Mishra, Prashant; Varuzhanyan, Grigor; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/z8gfq-2fc82", "eprint_id": 70330, "eprint_status": "archive", "datestamp": "2023-08-20 13:43:04", "lastmod": "2023-10-20 22:11:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Cheng-Chun-Ting", "name": { "family": "Cheng", "given": "Chun-Ting" } }, { "id": "Kuo-Ching-Ying", "name": { "family": "Kuo", "given": "Ching-Ying" } }, { "id": "Ouyang-Ching", "name": { "family": "Ouyang", "given": "Ching" } }, { "id": "Li-Chien-Feng", "name": { "family": "Li", "given": "Chien-Feng" } }, { "id": "Chung-Yiyin", "name": { "family": "Chung", "given": "Yiyin" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Kung-Hsing-Jien", "name": { "family": "Kung", "given": "Hsing-Jien" } }, { "id": "Ann-David-K", "name": { "family": "Ann", "given": "David K." } } ] }, "title": "Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 American Association for Cancer Research. \n\nReceived October 20, 2015; revised May 26, 2016; accepted June 15, 2016; published Online First June 30, 2016. \n\nNo potential conflicts of interest were disclosed.\n\nAuthors' Contributions:\nConception and design: C.-T. Cheng, C.-Y. Kuo, C.-F. Li, D.K. Ann\nDevelopment of methodology: C.-T. Cheng, C.-Y. Kuo, Y. Chung, D.K. Ann\nAcquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C.-T. Cheng, C.-Y. Kuo, C. Ouyang, C.-F. Li, Y. Chung\nAnalysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C.-T. Cheng, C.-Y. Kuo, C. Ouyang, C.-F. Li, D.C. Chan, H.-J. Kung, D.K. Ann\nWriting, review, and/or revision of the manuscript: C.-T. Cheng, C.-Y. Kuo, C. Ouyang, D.C. Chan, H.-J. Kung, D.K. Ann\nAdministrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.-T. Cheng, C. Ouyang, D.K. Ann\nStudy supervision: C.-T. Cheng, D.K. Ann\n\nThis study was financially supported by National Institute of Health Research Grants R01DE10742, R01DE14183, and The Mary Kay Foundation Research Grant number 005-13 (D.K. Ann), Ministry of Health and Welfare Research Grant MOHW103-TD-M-111-102001 (C.-F. Li), R01CA165263, R01CA150197, MOHW104-TDU-M-212-13304, MOST102-2320-B-400-018-MY3, MOST104-2321-B-400-009, NHRI05A1-MGPP15-014 (H.-J. Kung), and P30CA33572. \n\nThe costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. \n\nWe are sincerely grateful to Drs. Emily Wang and Art Riggs for their helpful suggestions and critical reading of manuscript, Ms. Lucy Brown of the Analytical Cytometry Core for flow cytometry analyses, Dr. Brian Armstrong and Ms. Tina Patel of the Light Microscopy Core for microscopy analyses, Mr. Austin Changou for processing time lapse imaging analyses, Drs. Xiwei Wu and Jinhui Wang and Mr. Charles Warden of Functional Genomics Core for RNA-seq data analyses, Ms. Tina Montgomery and Ms. Sofia Loera of Pathology Core for immunohistochemical analyses, Dr. Tzu-Ju Chen for pathological evaluation, Drs. Marcia Miller, Zhuo Li, and Ricardo Zerda of Electron Microscopy Core and Mr. Kevin Chi for EM image analysis and members of Dr. Ann's laboratory for helpful discussions and Dr. Nancy Linford for editing.\n\nAccepted Version - 0008-5472.CAN-15-2921.full.pdf
Supplemental Material - 157219_2_supp_3509776_474zs1.docx
Supplemental Material - 157219_2_supp_3509784_575zs2.pdf
Supplemental Material - 157219_2_video_3509799_l7lzll.mov
Supplemental Material - 157219_2_video_3509800_t7tztt.mov
Supplemental Material - 157219_2_video_3509801_w7wzww.mov
Supplemental Material - 157219_2_video_3509802_f7fzff.mov
", "abstract": "Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473 phosphorylation limited mitochondrial hyperfusion in glucose-starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress.", "date": "2016-09-01", "date_type": "published", "publication": "Cancer Research", "volume": "76", "number": "17", "publisher": "American Association for Cancer Research", "pagerange": "5006-5018", "id_number": "CaltechAUTHORS:20160914-080907190", "issn": "0008-5472", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160914-080907190", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01DE10742" }, { "agency": "NIH", "grant_number": "R01DE14183" }, { "agency": "Mary Kay Foundation", "grant_number": "005-13" }, { "agency": "Ministry of Health and Welfare (Taipei)", "grant_number": "MOHW103-TD-M-111-102001" }, { "agency": "NIH", "grant_number": "R01CA165263" }, { "agency": "NIH", "grant_number": "R01CA150197" }, { "agency": "Ministry of Health and Welfare (Taipei)", "grant_number": "MOHW104-TDU-M-212-13304" }, { "agency": "Ministry of Science and Technology (Taipei)", "grant_number": "MOST102-2320-B-400-018-MY3" }, { "agency": "Ministry of Science and Technology (Taipei)", "grant_number": "MOST104-2321-B-400-009" }, { "agency": "NIH", "grant_number": "NHRI05A1-MGPP15-014" }, { "agency": "National Cancer Institute", "grant_number": "P30CA33572" } ] }, "doi": "10.1158/0008-5472.CAN-15-2921", "pmcid": "PMC5316485", "primary_object": { "basename": "157219_2_video_3509801_w7wzww.mov", "url": "https://authors.library.caltech.edu/records/z8gfq-2fc82/files/157219_2_video_3509801_w7wzww.mov" }, "related_objects": [ { "basename": "157219_2_video_3509802_f7fzff.mov", "url": "https://authors.library.caltech.edu/records/z8gfq-2fc82/files/157219_2_video_3509802_f7fzff.mov" }, { "basename": "0008-5472.CAN-15-2921.full.pdf", "url": "https://authors.library.caltech.edu/records/z8gfq-2fc82/files/0008-5472.CAN-15-2921.full.pdf" }, { "basename": "157219_2_supp_3509776_474zs1.docx", "url": "https://authors.library.caltech.edu/records/z8gfq-2fc82/files/157219_2_supp_3509776_474zs1.docx" }, { "basename": "157219_2_supp_3509784_575zs2.pdf", "url": "https://authors.library.caltech.edu/records/z8gfq-2fc82/files/157219_2_supp_3509784_575zs2.pdf" }, { "basename": "157219_2_video_3509799_l7lzll.mov", "url": "https://authors.library.caltech.edu/records/z8gfq-2fc82/files/157219_2_video_3509799_l7lzll.mov" }, { "basename": "157219_2_video_3509800_t7tztt.mov", "url": "https://authors.library.caltech.edu/records/z8gfq-2fc82/files/157219_2_video_3509800_t7tztt.mov" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Cheng, Chun-Ting; Kuo, Ching-Ying; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/46t6w-93r57", "eprint_id": 66730, "eprint_status": "archive", "datestamp": "2023-08-22 18:21:33", "lastmod": "2023-10-18 18:45:11", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Fahrner-Jill-A", "name": { "family": "Fahrner", "given": "Jill A." } }, { "id": "Liu-Raymond", "name": { "family": "Liu", "given": "Raymond" } }, { "id": "Perry-Michael-Scott", "name": { "family": "Perry", "given": "Michael Scott" } }, { "id": "Klein-Jessica", "name": { "family": "Klein", "given": "Jessica" }, "orcid": "0000-0002-0529-9406" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "A novel de novo dominant negative mutation in DNM1L impairs mitochondrial fission and presents as childhood epileptic encephalopathy", "ispublished": "pub", "full_text_status": "public", "keywords": "DLP1; DNM1L; DRP1; developmental regression; epileptic encephalopathy; fission; mitochondria; seizures", "note": "\u00a9 2016 Wiley Periodicals, Inc. \n\nIssue online: 13 July 2016; Version of record online: 4 May 2016; Manuscript Accepted: 17 April 2016; Manuscript Received: 19 January 2016. \n\nWe first and foremost thank the patients and their families for permission to publish this work. We thank Zhiyv Niu, PhD, FACMG, for connecting the authors. We thank Vera Joanna Burton, MD, PhD, and Thangamadhan Bosemani, MBBS, for assistance with obtaining MR images. This work was supported by NIH grant GM110039. \n\nThe authors have no conflicts of interest to declare.\n\nAccepted Version - nihms-826390.pdf
", "abstract": "DNM1L encodes dynamin-related protein 1 (DRP1/DLP1), a key component of the mitochondrial fission machinery that is essential for proper functioning of the mammalian brain. Previously reported probands with de novo missense mutations in DNM1L presented in the first year of life with severe encephalopathy and refractory epilepsy, with several dying within the first several weeks after birth. In contrast, we report identical novel missense mutations in DNM1L in two unrelated probands who experienced normal development for several years before presenting with refractory focal status epilepticus and subsequent rapid neurological decline. We expand the phenotype of DNM1L-related mitochondrial fission defects, reveal common unique clinical characteristics and imaging findings, and compare the cellular impact of this novel mutation to the previously reported A395D lethal variant. We demonstrate that our R403C mutation, which resides in the assembly region of DRP1, acts by a dominant-negative mechanism and reduces oligomerization, mitochondrial fission activity, and mitochondrial recruitment of DRP1, but to a lesser extent compared to the A395D mutation. In contrast to the initial report of neonatal lethality resulting from DNM1L mutation and DRP1 dysfunction, our results show that milder DRP1 impairment is compatible with normal early development and subsequently results in a distinct set of neurological findings. In addition, we identify a common pathogenic mechanism whereby DNM1L mutations impair mitochondrial fission.", "date": "2016-08", "date_type": "published", "publication": "American Journal of Medical Genetics Part A", "volume": "170", "number": "8", "publisher": "Wiley", "pagerange": "2002-2011", "id_number": "CaltechAUTHORS:20160509-092215894", "issn": "1552-4825", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160509-092215894", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM110039" } ] }, "doi": "10.1002/ajmg.a.37721", "pmcid": "PMC5100740", "primary_object": { "basename": "nihms-826390.pdf", "url": "https://authors.library.caltech.edu/records/46t6w-93r57/files/nihms-826390.pdf" }, "resource_type": "article", "pub_year": "2016", "author_list": "Fahrner, Jill A.; Liu, Raymond; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/f58jj-k8p83", "eprint_id": 64462, "eprint_status": "archive", "datestamp": "2023-08-20 10:18:42", "lastmod": "2023-10-17 21:25:20", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Mishra-Prashant", "name": { "family": "Mishra", "given": "Prashant" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Metabolic regulation of mitochondrial dynamics", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 Mishra and Chan This article is distributed under the terms of an Attribution\u2013Noncommercial\u2013Share Alike\u2013No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution\u2013Noncommercial\u2013Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses by-nc-sa/3.0/). \n\nSubmitted: 9 November 2015; Accepted: 6 January 2016; Published February 8, 2016. \n\nThis work was supported by grants from the National Institutes of Health (GM110039) and the Muscular Dystrophy Association. \n\nThe authors declare no competing financial interests.\n\nPublished - J_Cell_Biol-2016-Mishra-379-87.pdf
", "abstract": "Mitochondria are renowned for their central bioenergetic role in eukaryotic cells, where they act as powerhouses to generate adenosine triphosphate from oxidation of nutrients. At the same time, these organelles are highly dynamic and undergo fusion, fission, transport, and degradation. Each of these dynamic processes is critical for maintaining a healthy mitochondrial population. Given the central metabolic function of mitochondria, it is not surprising that mitochondrial dynamics and bioenergetics reciprocally influence each other. We review the dynamic properties of mitochondria, with an emphasis on how these processes respond to cellular signaling events and how they affect metabolism.", "date": "2016-02-15", "date_type": "published", "publication": "Journal of Cell Biology", "volume": "212", "number": "4", "publisher": "Rockefeller University Press", "pagerange": "379-387", "id_number": "CaltechAUTHORS:20160212-094911928", "issn": "0021-9525", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160212-094911928", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM110039" }, { "agency": "Muscular Dystrophy Association" } ] }, "doi": "10.1083/jcb.201511036", "pmcid": "PMC4754720", "primary_object": { "basename": "J_Cell_Biol-2016-Mishra-379-87.pdf", "url": "https://authors.library.caltech.edu/records/f58jj-k8p83/files/J_Cell_Biol-2016-Mishra-379-87.pdf" }, "resource_type": "article", "pub_year": "2016", "author_list": "Mishra, Prashant and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/3dczv-rp187", "eprint_id": 64149, "eprint_status": "archive", "datestamp": "2023-08-20 09:56:24", "lastmod": "2023-10-17 19:33:07", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Toyama-Erin-Quan", "name": { "family": "Toyama", "given": "Erin Quan" } }, { "id": "Herzig-Sebastien", "name": { "family": "Herzig", "given": "Sebastien" } }, { "id": "Courchet-Julien", "name": { "family": "Courchet", "given": "Julien" } }, { "id": "Lewis-Tommy-L-Jr", "name": { "family": "Lewis", "given": "Tommy L., Jr." } }, { "id": "Los\u00f3n-Oliver-C", "name": { "family": "Los\u00f3n", "given": "Oliver C." } }, { "id": "Hellberg-Kristina", "name": { "family": "Hellberg", "given": "Kristina" } }, { "id": "Young-Nathan-P", "name": { "family": "Young", "given": "Nathan P." } }, { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Polleux-Franck", "name": { "family": "Polleux", "given": "Franck" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Shaw-Reuben-J", "name": { "family": "Shaw", "given": "Reuben J." } } ] }, "title": "AMP-activated protein kinase mediates mitochondrial fission in response to energy stress", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 American Association for the Advancement of Science. \n\nReceived 28 April 2015; accepted 9 December 2015. \n\nThis research was supported by NIH grants R01DK080425, R01CA172229, and P01 CA120964 to R.J.S; R01GM062967 and R01GM110039 to D.C.C; R01NS089456 to F.P.; and K99NS091526 to T.L.L. Work in the laboratory of R.J.S. was also supported in part by the Leona M. and Harry B. Helmsley Charitable Trust (grant 2012-PG-MED002). E.Q.T. and N.P.Y. were supported by American Cancer Society fellowships (122123-PF-12-029-01-TBE and 123016-PF-PF-12-191-01-TBE, respectively). S.H. was supported by a European Molecular Biology Organization (EMBO) Long Term Fellowship (ALTF 1101-2013). K.H. was funded by a George E. Hewitt Foundation for Medical Research fellowship. O.C.L. was supported by an American Physiological Society William Townsend Porter predoctoral fellowship. R.J.S. is the William R. Brody Chair at the Salk Institute and a Howard Hughes Medical Institute Early Career Scientist. We thank A. Singh and G. Kasof at Cell Signaling Technology for developing the antibody to MFF P-Ser172 in conjunction with E.Q.T. and R.J.S. We thank the Waitt Biophotonics Core and Flow Cytometry Core at the Salk Institute for use of their instruments, which are supported by the Salk Institute (grant CCSG P30 CA014195). We thank C. Merkwirth and M. Adams for helpful discussions and M. Chun for critical reading of the manuscript.\n\nAccepted Version - nihms-778814.pdf
Supplemental Material - aab4138-Toyama-SM-movie-S1.mov
Supplemental Material - aab4138-Toyama-SM-movie-S2.mov
Supplemental Material - aab4138-Toyama-SM-movie-S3.mov
Supplemental Material - aab4138-Toyama-SM-movie-S4.mov
Supplemental Material - aab4138-Toyama-SM-movie-S5.mov
Supplemental Material - aab4138-Toyama-SM.pdf
", "abstract": "Mitochondria undergo fragmentation in response to electron transport chain (ETC) poisons and mitochondrial DNA\u2013linked disease mutations, yet how these stimuli mechanistically connect to the mitochondrial fission and fusion machinery is poorly understood. We found that the energy-sensing adenosine monophosphate (AMP)\u2013activated protein kinase (AMPK) is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with ETC inhibitors. Moreover, direct pharmacological activation of AMPK was sufficient to rapidly promote mitochondrial fragmentation even in the absence of mitochondrial stress. A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. Nonphosphorylatable and phosphomimetic alleles of the AMPK sites in MFF revealed that it is a key effector of AMPK-mediated mitochondrial fission.", "date": "2016-01-15", "date_type": "published", "publication": "Science", "volume": "351", "number": "6270", "publisher": "American Association for the Advancement of Science", "pagerange": "275-281", "id_number": "CaltechAUTHORS:20160202-084338645", "issn": "0036-8075", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160202-084338645", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01DK080425" }, { "agency": "NIH", "grant_number": "R01CA172229" }, { "agency": "NIH", "grant_number": "P01 CA120964" }, { "agency": "NIH", "grant_number": "R01GM062967" }, { "agency": "NIH", "grant_number": "R01GM110039" }, { "agency": "NIH", "grant_number": "R01NS089456" }, { "agency": "NIH", "grant_number": "K99NS091526" }, { "agency": "Leona M. and Harry B. Helmsley Charitable Trust", "grant_number": "2012-PG-MED002" }, { "agency": "American Cancer Society", "grant_number": "122123-PF-12-029-01-TBE" }, { "agency": "American Cancer Society", "grant_number": "123016-PF-PF-12-191-01-TBE" }, { "agency": "European Molecular Biology Organization (EMBO)", "grant_number": "ALTF 1101-2013" }, { "agency": "George E. Hewitt Foundation" }, { "agency": "American Physiological Society" }, { "agency": "Salk Institute", "grant_number": "CCSG P30 CA014195" }, { "agency": "Howard Hughes Medical Institute (HHMI)" } ] }, "doi": "10.1126/science.aab4138", "pmcid": "PMC4852862", "primary_object": { "basename": "aab4138-Toyama-SM-movie-S2.mov", "url": "https://authors.library.caltech.edu/records/3dczv-rp187/files/aab4138-Toyama-SM-movie-S2.mov" }, "related_objects": [ { "basename": "aab4138-Toyama-SM-movie-S3.mov", "url": "https://authors.library.caltech.edu/records/3dczv-rp187/files/aab4138-Toyama-SM-movie-S3.mov" }, { "basename": "aab4138-Toyama-SM-movie-S4.mov", "url": "https://authors.library.caltech.edu/records/3dczv-rp187/files/aab4138-Toyama-SM-movie-S4.mov" }, { "basename": "aab4138-Toyama-SM-movie-S5.mov", "url": "https://authors.library.caltech.edu/records/3dczv-rp187/files/aab4138-Toyama-SM-movie-S5.mov" }, { "basename": "aab4138-Toyama-SM.pdf", "url": "https://authors.library.caltech.edu/records/3dczv-rp187/files/aab4138-Toyama-SM.pdf" }, { "basename": "nihms-778814.pdf", "url": "https://authors.library.caltech.edu/records/3dczv-rp187/files/nihms-778814.pdf" }, { "basename": "aab4138-Toyama-SM-movie-S1.mov", "url": "https://authors.library.caltech.edu/records/3dczv-rp187/files/aab4138-Toyama-SM-movie-S1.mov" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Toyama, Erin Quan; Herzig, Sebastien; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/2aq8a-63t19", "eprint_id": 61758, "eprint_status": "archive", "datestamp": "2023-08-20 09:23:49", "lastmod": "2023-10-25 15:42:36", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Mishra-Prashant", "name": { "family": "Mishra", "given": "Prashant" } }, { "id": "Varuzhanyan-Grigor", "name": { "family": "Varuzhanyan", "given": "Grigor" }, "orcid": "0000-0001-6165-0857" }, { "id": "Pham-Anh-H", "name": { "family": "Pham", "given": "Anh H." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial Dynamics Is a Distinguishing Feature of Skeletal Muscle Fiber Types and Regulates Organellar Compartmentalization", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2015 Elsevier Inc. \n\nReceived: June 18, 2015; Revised: September 8, 2015; Accepted: September 23, 2015; Published: October 22, 2015. \n\nWe thank Alexander van der Bliek for providing the \u03b1-Mff antibody. We are grateful to Hsiuchen Chen for help with experiments using Mfn1/2 and Mff mutant mice. This work was supported by grants from the NIH (GM062967) and the Muscular Dystrophy Association. P.M. was supported by a Baxter Senior Postdoctoral fellowship. G.V. was supported by grants from the NIH (National Research Service Award T32 GM0076162) and the California Institute for Regenerative Medicine (Stem Cell Bridges Program, TB1-01176). We thank members of the D.C.C. lab for helpful discussions and comments on the manuscript. \n\nAuthor Contributions: P.M., G.V., A.H.P., and D.C.C. conceived and designed experiments. P.M. and A.H.P. performed experiments relating to mitochondrial morphology. G.V. and A.H.P. performed experiments relating to mitochondrial domains. P.M. and D.C.C. wrote the manuscript.\n\nAccepted Version - nihms728305.pdf
Supplemental Material - mmc1.pdf
", "abstract": "Skeletal muscle fibers differentiate into specific fiber types with distinct metabolic properties determined by their reliance on oxidative phosphorylation (OXPHOS). Using in vivo approaches, we find that OXPHOS-dependent fibers, compared to glycolytic fibers, contain elongated mitochondrial networks with higher fusion rates that are dependent on the mitofusins Mfn1 and Mfn2. Switching of a glycolytic fiber to an oxidative IIA type is associated with elongation of mitochondria, suggesting that mitochondrial fusion is linked to metabolic state. Furthermore, we reveal that mitochondrial proteins are compartmentalized to discrete domains centered around their nuclei of origin. The domain dimensions are dependent on fiber type and are regulated by the mitochondrial dynamics proteins Mfn1, Mfn2, and Mff. Our results indicate that mitochondrial dynamics is tailored to fiber type physiology and provides a rationale for the segmental defects characteristic of aged and diseased muscle fibers.", "date": "2015-12-01", "date_type": "published", "publication": "Cell Metabolism", "volume": "22", "number": "6", "publisher": "Cell Press", "pagerange": "1033-1044", "id_number": "CaltechAUTHORS:20151102-084437357", "issn": "1550-4131", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20151102-084437357", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "Muscular Dystrophy Association" }, { "agency": "Baxter Foundation" }, { "agency": "NIH", "grant_number": "T32 GM0076162" }, { "agency": "California Institute for Regenerative Medicine (CIRM)", "grant_number": "TB1-01176" } ] }, "doi": "10.1016/j.cmet.2015.09.027", "pmcid": "PMC4670593", "primary_object": { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/2aq8a-63t19/files/mmc1.pdf" }, "related_objects": [ { "basename": "nihms728305.pdf", "url": "https://authors.library.caltech.edu/records/2aq8a-63t19/files/nihms728305.pdf" } ], "resource_type": "article", "pub_year": "2015", "author_list": "Mishra, Prashant; Varuzhanyan, Grigor; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/n5mkn-t0003", "eprint_id": 61005, "eprint_status": "archive", "datestamp": "2023-08-20 09:23:31", "lastmod": "2023-10-24 23:18:14", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Liu-Raymond", "name": { "family": "Liu", "given": "Raymond" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "The mitochondrial fission receptor Mff selectively recruits oligomerized Drp1", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2015 by The American Society for Cell Biology. Under the License and Publishing Agreement, authors grant to the general public, effective two months after publication of (i.e.,. the appearance of) the edited manuscript in an online issue of MBoC, the nonexclusive right to copy, distribute, or display the manuscript subject to the terms of the Creative Commons\u2013Noncommercial\u2013Share Alike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0).\n\nPublished online before print October 7, 2015.\n\nR.L. was supported by a National Science Foundation Graduate Research Fellowship Program award (1144469). We are grateful to Katsuyoshi Mihara (Kyushu University, Fukuoka, Japan) for the Drp1-null MEFs. This work was supported by NIH RO1 grant GM110039.\n\nPublished - Mol._Biol._Cell-2015-Liu-4466-77.pdf
Supplemental Material - E15-08-0591-revSupp.pdf
", "abstract": "Dynamin-related protein 1 (Drp1) is the GTP-hydrolyzing mechanoenzyme that catalyzes mitochondrial fission in the cell. Residing in the cytosol as dimers and tetramers, Drp1 is recruited by receptors on the mitochondrial outer membrane, where it further assembles into a helical ring that drives division via GTP-dependent constriction. The Drp1 receptor Mff is a major regulator of mitochondrial fission, and its overexpression results in increased fission. In contrast, the alternative Drp1 receptors MiD51 and MiD49 appear to recruit inactive forms of Drp1, because their overexpression inhibits fission. Using genetic and biochemical assays, we studied the interaction of Drp1 with Mff. We show the insert B region of Drp1 inhibits Mff-Drp1 interactions, such that recombinant Drp1 mutants lacking insert B form a stable complex with Mff. Mff cannot bind to assembly-deficient mutants of Drp1, suggesting that Mff selectively interacts with higher order complexes of Drp1. In contrast, the alternative Drp1 receptors MiD51 and MiD49 can recruit Drp1 dimers. Therefore, Drp1 recruitment by Mff versus MiD51 and MiD49 may result in different outcomes because they recruit different subpopulations of Drp1 from the cytosol.", "date": "2015-12-01", "date_type": "published", "publication": "Molecular Biology of the Cell", "volume": "26", "number": "24", "publisher": "American Society for Cell Biology", "pagerange": "4466-4477", "id_number": "CaltechAUTHORS:20151012-135444280", "issn": "1059-1524", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20151012-135444280", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF Graduate Research Fellowship", "grant_number": "1144469" }, { "agency": "NIH", "grant_number": "GM110039" } ] }, "doi": "10.1091/mbc.E15-08-0591", "pmcid": "PMC4666140", "primary_object": { "basename": "E15-08-0591-revSupp.pdf", "url": "https://authors.library.caltech.edu/records/n5mkn-t0003/files/E15-08-0591-revSupp.pdf" }, "related_objects": [ { "basename": "Mol._Biol._Cell-2015-Liu-4466-77.pdf", "url": "https://authors.library.caltech.edu/records/n5mkn-t0003/files/Mol._Biol._Cell-2015-Liu-4466-77.pdf" } ], "resource_type": "article", "pub_year": "2015", "author_list": "Liu, Raymond and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/44asg-2ck36", "eprint_id": 62426, "eprint_status": "archive", "datestamp": "2023-08-20 09:09:48", "lastmod": "2023-10-25 17:09:00", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Ren-Shuxun", "name": { "family": "Ren", "given": "Shuxun" } }, { "id": "Clish-Clary", "name": { "family": "Clish", "given": "Clary" }, "orcid": "0000-0001-8259-9245" }, { "id": "Jain-Mohit", "name": { "family": "Jain", "given": "Mohit" } }, { "id": "Mootha-Vamsi", "name": { "family": "Mootha", "given": "Vamsi" }, "orcid": "0000-0001-9924-642X" }, { "id": "McCaffery-J-Michael", "name": { "family": "McCaffery", "given": "J. Michael" }, "orcid": "0000-0001-7153-9933" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2015 Chen et al. This article is distributed under the terms of an Attribution\u2013Noncommercial\u2013Share Alike\u2013No Mirror Sites license for the first six months after the publication date (see http://www.rupress .org /terms). After six months it is available under a Creative Commons License (Attribution\u2013Noncommercial\u2013Share Alike 3.0 Unported license, as described at http://creativecommons.org /licenses /by-nc-sa/3.0/). \n\nSubmitted: 8 July 2015; Accepted: 15 October 2015; Published November 23, 2015. \n\nWe thank Maria Jordan and Dr. Kenneth Roos for performing echocardiography on 13\u201314-wk-old mice. We are grateful to Dr. Prashant Mishra for many hours of technical instruction and discussion. \n\nThis work was supported by grant RO1GM062967 (to D.C. Chan). \n\nThe authors declare no competing financial interests.\n\nPublished - J_Cell_Biol-2015-Chen-795-805.pdf
Supplemental Material - JCB_201507035_V1.mp4
Supplemental Material - JCB_201507035_sm.pdf
", "abstract": "Defects in mitochondrial fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the mitochondrial fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of mitochondrial fusion and fission can restore tissue integrity and mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of fusion and fission is cell type specific.", "date": "2015-11-23", "date_type": "published", "publication": "Journal of Cell Biology", "volume": "211", "number": "4", "publisher": "Rockefeller University Press", "pagerange": "795-805", "id_number": "CaltechAUTHORS:20151125-103607166", "issn": "0021-9525", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20151125-103607166", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "RO1GM062967" } ] }, "doi": "10.1083/jcb.201507035", "pmcid": "PMC4657172", "primary_object": { "basename": "JCB_201507035_V1.mp4", "url": "https://authors.library.caltech.edu/records/44asg-2ck36/files/JCB_201507035_V1.mp4" }, "related_objects": [ { "basename": "JCB_201507035_sm.pdf", "url": "https://authors.library.caltech.edu/records/44asg-2ck36/files/JCB_201507035_sm.pdf" }, { "basename": "J_Cell_Biol-2015-Chen-795-805.pdf", "url": "https://authors.library.caltech.edu/records/44asg-2ck36/files/J_Cell_Biol-2015-Chen-795-805.pdf" } ], "resource_type": "article", "pub_year": "2015", "author_list": "Chen, Hsiuchen; Ren, Shuxun; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/e3mph-z5p90", "eprint_id": 58961, "eprint_status": "archive", "datestamp": "2023-08-20 08:20:24", "lastmod": "2023-10-23 19:55:05", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hashimoto-Masami", "name": { "family": "Hashimoto", "given": "Masami" } }, { "id": "Bacman-S-R", "name": { "family": "Bacman", "given": "Sandra R." } }, { "id": "Peralta-S", "name": { "family": "Peralta", "given": "Susana" } }, { "id": "Falk-M-J", "name": { "family": "Falk", "given": "Marni J." } }, { "id": "Chomyn-A", "name": { "family": "Chomyn", "given": "Anne" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Williams-S-L", "name": { "family": "Williams", "given": "Sion L." } }, { "id": "Moraes-C-T", "name": { "family": "Moraes", "given": "Carlos T." } } ] }, "title": "MitoTALENs: A general approach to reduce mutant mtDNA loads and restore oxidative phosphorylation function in mitochondrial diseases", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2015 American Society of Gene & Cell Therapy. Under a Creative Commons license -- Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) \n\nReceived 22 April 2015; Accepted 21 June 2015; Accepted article preview online 10 July 2015. \n\nWe are grateful to the skilled assistance of the Flow Cytometry Core Facility for the cell sorting services and the Oncogenomics Core Facility for the Sanger sequencing services at the Sylvester Comprehensive Cancer Center, University of Miami. This work was supported by donations from Mr. Ron Biscardi, the JDM Fund and grants from the NIH (5R01EY010804 and 5R01NS079965), the Muscular Dystrophy Association and the United Mitochondrial Disease Foundation.\n\nSupplemental Material - 1-s2.0-S1525001616302908-mmc1.pdf
", "abstract": "We have designed mitochondrially targeted Transcription Activator-Like Effector Nucleases or mitoTALENs to cleave specific sequences in the mitochondrial DNA (mtDNA) with the goal of eliminating mtDNA carrying pathogenic point mutations. To test the generality of the approach we designed mitoTALENs to target two relatively common pathogenic mtDNA point mutations associated with mitochondrial diseases: the m.8344A>G tRNA^(Lys) gene mutation associated with Myoclonic Epilepsy with Ragged-Red Fibers (MERRF) and the m.13513G>A ND5 mutation associated with MELAS/Leigh Syndrome. Transmitochondrial cybrid cells harbouring the respective heteroplasmic mtDNA mutations were transfected with the respective mitoTALEN and analysed after different time periods. MitoTALENs efficiently reduced the levels of the targeted pathogenic mtDNAs in the respective cell lines. Functional assays showed that cells with heteroplasmic mutant mtDNA were able to recover respiratory capacity and oxidative phosphorylation enzymes activity after transfection with the mitoTALEN. To improve the design in the context of the low complexity of mtDNA, we designed shorter versions of the mitoTALEN specific for the MERRF m.8344A>G mutation. These shorter mitoTALENs also eliminated the mutant mtDNA. These reductions in size improve our ability to package these large sequences into viral vectors, bringing the use of these genetic tools closer to clinical trials.", "date": "2015-10", "date_type": "published", "publication": "Molecular Therapy", "volume": "23", "number": "10", "publisher": "American Society of Gene & Cell Therapy", "pagerange": "1592-1599", "id_number": "CaltechAUTHORS:20150721-100512606", "issn": "1525-0016", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150721-100512606", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "JDM Fund" }, { "agency": "NIH", "grant_number": "5R01EY010804" }, { "agency": "NIH", "grant_number": "5R01NS079965" }, { "agency": "Muscular Dystrophy Association" }, { "agency": "United Mitochondrial Disease Foundation" }, { "agency": "Ron Biscardi" } ] }, "doi": "10.1038/mt.2015.126", "pmcid": "PMC4817924", "primary_object": { "basename": "1-s2.0-S1525001616302908-mmc1.pdf", "url": "https://authors.library.caltech.edu/records/e3mph-z5p90/files/1-s2.0-S1525001616302908-mmc1.pdf" }, "related_objects": [ { "basename": "MitoTALEN__A_General_Approach_to_Reduce_Mutant_mtDNA_Loads_and_Restore_Oxidative_Phosphorylation_Function_in_Mitochondrial_Diseases.pdf", "url": "https://authors.library.caltech.edu/records/e3mph-z5p90/files/MitoTALEN__A_General_Approach_to_Reduce_Mutant_mtDNA_Loads_and_Restore_Oxidative_Phosphorylation_Function_in_Mitochondrial_Diseases.pdf" } ], "resource_type": "article", "pub_year": "2015", "author_list": "Hashimoto, Masami; Bacman, Sandra R.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/jp932-cne52", "eprint_id": 53898, "eprint_status": "archive", "datestamp": "2023-08-22 15:02:16", "lastmod": "2023-10-19 22:21:42", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Los\u00f3n-O-C", "name": { "family": "Los\u00f3n", "given": "Oliver C." } }, { "id": "Meng-Shuxia", "name": { "family": "Meng", "given": "Shuxia" } }, { "id": "Ngo-Huu-B", "name": { "family": "Ngo", "given": "Huu" } }, { "id": "Liu-Raymond", "name": { "family": "Liu", "given": "Raymond" } }, { "id": "Kaiser-J-T", "name": { "family": "Kaiser", "given": "Jens T." }, "orcid": "0000-0002-5948-5212" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Crystal structure and functional analysis of MiD49, a receptor for the mitochondrial fission protein Drp1", "ispublished": "pub", "full_text_status": "public", "keywords": "mitochondrial fission; mitochondrial dynamics; MiD49; dynamin-related protein", "note": "\u00a9 2014 The Protein Society. Received 24 October 2014; Revised 17 December 2014; Accepted 18 December 2014. Article first published online: 14 Jan 2015.\n\nThe authors acknowledge the Gordon and Betty Moore Foundation, the Beckman Institute, and the Sanofi-Aventis Bioengineering Research Program at Caltech for their generous support of the Molecular Observatory at Caltech. Operations at SSRL are supported by the US DOE and NIH. This wol'k was supported by the National Institutes of Health (GM110039). OCL was supported by a R. L. Kirschstein National Research Service Award (5F31GM089327) and an American Physiological Society William Townsend Porter Pre-doctoral fellowship.\n\nSupplemental Material - pro2629-sup-0001-suppinfo.pdf
", "abstract": "Mitochondrial fission requires recruitment of dynamin-related protein 1 (Drp1) to the mitochondrial surface, where assembly leads to activation of its GTP-dependent scission function. MiD49 and MiD51 are two receptors on the mitochondrial outer membrane that can recruit Drp1 to facilitate mitochondrial fission. Structural studies indicated that MiD51 has a variant nucleotidyl transferase fold that binds an ADP co-factor essential for activation of Drp1 function. MiD49 shares sequence homology with MiD51 and regulates Drp1 function. However, it is unknown if MiD49 binds an analogous co-factor. Because MiD49 does not readily crystallize, we used structural predictions and biochemical screening to identify a surface entropy reduction mutant that facilitated crystallization. Using molecular replacement, we determined the atomic structure of MiD49 to 2.4 \u00c5. Like MiD51, MiD49 contains a nucleotidyl transferase domain; however, the electron density provides no evidence for a small-molecule ligand. Structural changes in the putative nucleotide-binding pocket make MiD49 incompatible with an extended ligand like ADP, and critical nucleotide-binding residues found in MiD51 are not conserved. MiD49 contains a surface loop that physically interacts with Drp1 and is necessary for Drp1 recruitment to the mitochondrial surface. Our results suggest a structural basis for the differential regulation of MiD51- versus MiD49-mediated fission.", "date": "2015-03", "date_type": "published", "publication": "Protein Science", "volume": "24", "number": "3", "publisher": "Wiley", "pagerange": "386-394", "id_number": "CaltechAUTHORS:20150120-150157635", "issn": "0961-8368", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150120-150157635", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Gordon and Betty Moore Foundation" }, { "agency": "Caltech Beckman Institute" }, { "agency": "Caltech Sanofi-Aventis Bioengineering Research Program" }, { "agency": "Department of Energy (DOE)" }, { "agency": "NIH", "grant_number": "GM110039" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5F31GM089327" }, { "agency": "American Physiological Society William Townsend Porter Predoctoral Fellowship" } ] }, "doi": "10.1002/pro.2629", "pmcid": "PMC4353364", "primary_object": { "basename": "pro2629-sup-0001-suppinfo.pdf", "url": "https://authors.library.caltech.edu/records/jp932-cne52/files/pro2629-sup-0001-suppinfo.pdf" }, "resource_type": "article", "pub_year": "2015", "author_list": "Los\u00f3n, Oliver C.; Meng, Shuxia; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/kvrhp-x5v27", "eprint_id": 53150, "eprint_status": "archive", "datestamp": "2023-08-20 04:03:18", "lastmod": "2023-10-19 14:36:10", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Carelli-V", "name": { "family": "Carelli", "given": "Valerio" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial DNA: Impacting Central and Peripheral Nervous Systems", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Elsevier Inc.\n\nAvailable online 17 December 2014.\n\nWork in the authors' laboratories is supported by HHMI (D.C.C.); NIH grants\nGM062967 (D.C.C.) and GM110039 (D.C.C.); Telethon grants GGP11182\n(V.C.) and GPP10005 (V.C); the Emilia-Romagna region program ER-MITO\n(V.C.); support of Fondazione Galletti (V.C.); and support from the patient's\nassociations MITOCON, UMDF, IFOND, Struggling Within Leber's, and\nThe Poincenot Family (V.C.). We are grateful to Maria Lucia Valentino (University\nof Bologna), Piero Barboni (Universit\u00e0 Vita-Salute San Raffaele), Alfredo A.\nSadun (Doheny Eye Institute, UCLA), and Fred Ross-Cisneros (Doheny Eye\nInstitute, UCLA) for providing clinical and histological images used in the\nfigures.\n\nAccepted Version - nihms645699.pdf
", "abstract": "Because of their high-energy metabolism, neurons are strictly dependent on mitochondria, which generate\ncellular ATP through oxidative phosphorylation. The mitochondrial genome encodes for critical components\nof the oxidative phosphorylation pathway machinery, and therefore, mutations in mitochondrial DNA\n(mtDNA) cause energy production defects that frequently have severe neurological manifestations. Here,\nwe review the principles of mitochondrial genetics and focus on prototypical mitochondrial diseases to\nillustrate how primary defects in mtDNA or secondary defects in mtDNA due to nuclear genome mutations\ncan cause prominent neurological and multisystem features. In addition, we discuss the pathophysiological\nmechanisms underlying mitochondrial diseases, the cellular mechanisms that protect mitochondrial\nintegrity, and the prospects for therapy.", "date": "2014-12-17", "date_type": "published", "publication": "Neuron", "volume": "84", "number": "6", "publisher": "Elsevier", "pagerange": "1126-1142", "id_number": "CaltechAUTHORS:20141223-110628282", "issn": "0896-6273", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141223-110628282", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "NIH", "grant_number": "GM110039" }, { "agency": "Telethon (Italy)", "grant_number": "GGP11182" }, { "agency": "Telethon (Italy)", "grant_number": "GPP10005" }, { "agency": "Emilia-Romagna Region Program" }, { "agency": "Fondazione Galletti" }, { "agency": "MITOCON" }, { "agency": "UMDF" }, { "agency": "IFOND" }, { "agency": "Struggling Within Leber's" }, { "agency": "Poincenot Family" } ] }, "doi": "10.1016/j.neuron.2014.11.022", "pmcid": "PMC4271190", "primary_object": { "basename": "nihms645699.pdf", "url": "https://authors.library.caltech.edu/records/kvrhp-x5v27/files/nihms645699.pdf" }, "resource_type": "article", "pub_year": "2014", "author_list": "Carelli, Valerio and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/fpxwt-ty836", "eprint_id": 51055, "eprint_status": "archive", "datestamp": "2023-08-20 03:05:51", "lastmod": "2023-10-18 16:00:06", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Mishra-P", "name": { "family": "Mishra", "given": "Prashant" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial dynamics and inheritance during cell division, development and disease", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Macmillan Publishers Limited.\n\nPublished online 17 September 2014.\n\nP.M. is supported by a Baxter Postdoctoral Fellowship. Work\nin laboratory of D.C.C. is supported by the US National\nInstitutes of Health grants GM062967 and GM110039, the\nMuscular Dystrophy Association and the Howard Hughes\nMedical Institute.\n\nThe authors declare no competing interests.\n\nAccepted Version - nihms644044.pdf
", "abstract": "During cell division, it is critical to properly partition functional sets of organelles to each daughter cell. The partitioning of mitochondria shares some common features with that of other organelles, particularly in the use of interactions with cytoskeletal elements to facilitate delivery to the daughter cells. However, mitochondria have unique features \u2014 including their own genome and a maternal mode of germline transmission \u2014 that place additional demands on this process. Consequently, mechanisms have evolved to regulate mitochondrial segregation during cell division, oogenesis, fertilization and tissue development, as well as to ensure the integrity of these organelles and their DNA, including fusion\u2013fission dynamics, organelle transport, mitophagy and genetic selection of functional genomes. Defects in these processes can lead to cell and tissue pathologies.", "date": "2014-10", "date_type": "published", "publication": "Nature Reviews. Molecular Cell Biology", "volume": "15", "number": "10", "publisher": "Nature Publishing Group", "pagerange": "634-646", "id_number": "CaltechAUTHORS:20141030-100627897", "issn": "1471-0072", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141030-100627897", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Baxter Postdoctoral Fellowship" }, { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "NIH", "grant_number": "GM110039" }, { "agency": "Muscular Dystrophy Association" }, { "agency": "Howard Hughes Medical Institute (HHMI)" } ] }, "doi": "10.1038/nrm3877", "pmcid": "PMC4250044", "primary_object": { "basename": "nihms644044.pdf", "url": "https://authors.library.caltech.edu/records/fpxwt-ty836/files/nihms644044.pdf" }, "resource_type": "article", "pub_year": "2014", "author_list": "Mishra, Prashant and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/mefc4-tdr41", "eprint_id": 46068, "eprint_status": "archive", "datestamp": "2023-08-20 01:50:46", "lastmod": "2023-10-26 18:39:43", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-Nickie-C", "name": { "family": "Chan", "given": "Nickie C." } }, { "id": "den-Besten-W", "name": { "family": "den Besten", "given": "Willem" } }, { "id": "Sweredoski-M-J", "name": { "family": "Sweredoski", "given": "Michael J." }, "orcid": "0000-0003-0878-3831" }, { "id": "Hess-S", "name": { "family": "Hess", "given": "Sonja" }, "orcid": "0000-0002-5904-9816" }, { "id": "Deshaies-R-J", "name": { "family": "Deshaies", "given": "Raymond J." }, "orcid": "0000-0002-3671-9354" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Degradation of the Deubiquitinating Enzyme USP33 is Mediated by p97 and the Ubiquitin Ligase HERC2", "ispublished": "pub", "full_text_status": "public", "keywords": "Protein degradation, ubiquitin ligase, ubiquitination, deubiquitinating enzyme, proteasome,\np97, HERC2, USP33", "note": "\u00a9 2014, The American Society for Biochemistry and Molecular Biology. \n\nReceived March 27, 2014. Accepted May 22, 2014. First Published on May 22, 2014. \n\nWe are grateful for help from the following: Tomohiko Ohta for HERC2 constructs that helped us to reconstruct full-length HERC2; William G. Kaelin Jr. for the 786-O and RCC4 cell lines; Tsui-Fen Chou (Harbor-UCLA Medical Center) for helpful discussions and reagents during the early stage of this work; Robert Graham (currently at University of Manchester) from the PEL for technical help with the mass spectrometry experiments; Michael Walters and Lev G. Lis (University of Minnesota) for NMS-873. The PEL is supported by the Gordon and Betty Moore Foundation through grant GBMF775 and the Beckman Institute. This work was funded by the Howard Hughes Medical Institute and NIH RO1 GM062967.\n\nPublished - J._Biol._Chem.-2014-Chan-19789-98.pdf
", "abstract": "Because the deubiquitinating enzyme USP33 is involved in several important cellular processes (\u03b2-adrenergic receptor recycling, centrosome amplification, RalB signaling, and cancer cell migration), its levels must be carefully regulated. Using quantitative mass spectrometry, we found that the intracellular level of USP33 is highly sensitive to the activity of p97. Knockdown or chemical inhibition of p97 causes robust accumulation of USP33 due to inhibition of its degradation. The p97 adaptor complex involved in this function is the Ufd1-Npl4 heterodimer. Furthermore, we identified HERC2, a HECT-domain-containing E3 ligase, as responsible for polyubiquitination of USP33. Inhibition of p97 causes accumulation of polyubiquitinated USP33, suggesting that p97 is required for post-ubiquitination processing. Thus, our study has identified several key molecules that control USP33 degradation within the ubiquitin-proteasome system.", "date": "2014-07-11", "date_type": "published", "publication": "Journal of Biological Chemistry", "volume": "289", "number": "28", "publisher": "American Society for Biochemistry and Molecular Biology", "pagerange": "19789-19798", "id_number": "CaltechAUTHORS:20140604-082523933", "issn": "0021-9258", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140604-082523933", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Gordon and Betty Moore Foundation", "grant_number": "GBMF775" }, { "agency": "Caltech Beckman Institute" }, { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "NIH", "grant_number": "RO1 GM062967" } ] }, "doi": "10.1074/jbc.M114.569392", "pmcid": "PMC4094088", "primary_object": { "basename": "J._Biol._Chem.-2014-Chan-19789-98.pdf", "url": "https://authors.library.caltech.edu/records/mefc4-tdr41/files/J._Biol._Chem.-2014-Chan-19789-98.pdf" }, "resource_type": "article", "pub_year": "2014", "author_list": "Chan, Nickie C.; den Besten, Willem; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/mn4mk-q4v28", "eprint_id": 44859, "eprint_status": "archive", "datestamp": "2023-08-20 00:18:50", "lastmod": "2023-10-26 17:00:35", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Mishra-P", "name": { "family": "Mishra", "given": "Prashant" } }, { "id": "Carelli-V", "name": { "family": "Carelli", "given": "Valerio" } }, { "id": "Manfredi-G", "name": { "family": "Manfredi", "given": "Giovanni" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Proteolytic Cleavage of Opa1 Stimulates Mitochondrial Inner Membrane Fusion and Couples Fusion to Oxidative Phosphorylation", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Elsevier Inc. Received: January 29, 2013. Revised: December 3, 2013. Accepted: January 27, 2014. Published: April 1, 2014. This work was supported by grant GM062967 from the National Institutes of Health. P.M. was supported by a fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. We thank Dr. Andrea Martinuzzi for construction of the ND1 cybrid, Dr. Carlos L\u03ccpez-Ot\u00edn for providing Oma1-null cells, and members of the Chan lab for helpful discussions and comments on the manuscript.\n\nAccepted Version - nihms577798.pdf
Supplemental Material - mmc1.pdf
", "abstract": "Mitochondrial fusion is essential for maintenance of mitochondrial function. The mitofusin GTPases control mitochondrial outer membrane fusion, whereas the dynamin-related GTPase Opa1 mediates inner membrane fusion. We show that mitochondrial inner membrane fusion is tuned by the level of oxidative phosphorylation (OXPHOS), whereas outer membrane fusion is insensitive. Consequently, cells from patients with pathogenic mtDNA mutations show a selective defect in mitochondrial inner membrane fusion. In elucidating the molecular mechanism of OXPHOS-stimulated fusion, we uncover that real-time proteolytic processing of Opa1 stimulates mitochondrial inner membrane fusion. OXPHOS-stimulated mitochondrial fusion operates through Yme1L, which cleaves Opa1 more efficiently under high OXPHOS conditions. Engineered cleavage of Opa1 is sufficient to mediate inner membrane fusion, regardless of respiratory state. Proteolytic cleavage therefore stimulates the membrane fusion activity of Opa1, and this feature is exploited to dynamically couple mitochondrial fusion to cellular metabolism.", "date": "2014-04-01", "date_type": "published", "publication": "Cell Metabolism", "volume": "19", "number": "4", "publisher": "Elsevier", "pagerange": "630-641", "id_number": "CaltechAUTHORS:20140410-115936273", "issn": "1550-4131", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140410-115936273", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "Jane Coffin Childs Memorial Fund for Medical Research" } ] }, "doi": "10.1016/j.cmet.2014.03.011", "pmcid": "PMC4018240", "primary_object": { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/mn4mk-q4v28/files/mmc1.pdf" }, "related_objects": [ { "basename": "nihms577798.pdf", "url": "https://authors.library.caltech.edu/records/mn4mk-q4v28/files/nihms577798.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Mishra, Prashant; Carelli, Valerio; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/8xjd9-v1h23", "eprint_id": 54428, "eprint_status": "archive", "datestamp": "2023-08-20 00:16:29", "lastmod": "2023-10-20 16:26:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Losn-O", "name": { "family": "Losn", "given": "Oliver" } }, { "id": "Rome-M-E", "name": { "family": "Rome", "given": "Michael" } }, { "id": "Kaiser-J-T", "name": { "family": "Kaiser", "given": "Jens" }, "orcid": "0000-0002-5948-5212" }, { "id": "Shan-S-O", "name": { "family": "Shan", "given": "Shu-ou" }, "orcid": "0000-0002-6526-1733" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Regulation of mitochondrial fission by MiD51", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2014 Federation of American Societies for Experimental Biology.", "abstract": "Mitochondrial fission requires the recruitment of dynamin-related protein 1 (Drp1) to mitochondria and activation of its GTP-dependent scission function. In mammals, the recruitment of Drp1 is primarily regulated by the outer membrane receptors Mff, MiD49 and MiD51, while Fis1 plays a minor role. We recently demonstrated that these receptors can function independently of one another to recruit Drp1 and mediate mitochondrial division. Intriguingly, exogenous expression of MiD49 and MiD51 causes constitutive recruitment of Drp1 but inhibits its scission activity. With mitochondrial stress, however, these receptors can rapidly activate pre-recruited Drp1 and cause rapid mitochondrial fragmentation independently of Fis1 and Mff. This behavior suggests an ability to sense mitochondrial function, but the molecular mechanism is unknown. To better understand the role of the MiDs in regulating mitochondrial fission, we produced recombinant protein pertaining to the cytosolic domain of each MiD, and performed crystallographic screens. We obtained crystals for MiD51 that diffracted to high resolution, and we were able to determine its structure. MiD51 possesses a nucleotidyl transferase fold and uses a variant set of residues to tightly bind a ligand. We have performed a structure-function analysis of MiD51 by mutating structurally implicated residues and studying their importance in vivo and in vitro to activate Drp1. Our analysis reveals how MiD51 activates mitochondrial fission during mitochondrial stress.", "date": "2014-04", "date_type": "published", "publication": "FASEB Journal", "volume": "28", "number": "1", "publisher": "Federation of American Societies for Experimental Biology", "pagerange": "757.1", "id_number": "CaltechAUTHORS:20150205-131139873", "issn": "0892-6638", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150205-131139873", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "resource_type": "article", "pub_year": "2014", "author_list": "Losn, Oliver; Rome, Michael; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/vfbc2-1p098", "eprint_id": 43840, "eprint_status": "archive", "datestamp": "2023-08-19 23:52:11", "lastmod": "2023-10-25 23:56:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Los\u00f3n-O-C", "name": { "family": "Los\u00f3n", "given": "Oliver C." } }, { "id": "Liu-Raymond", "name": { "family": "Liu", "given": "Raymond" } }, { "id": "Rome-M-E", "name": { "family": "Rome", "given": "Michael E." } }, { "id": "Meng-Shuxia", "name": { "family": "Meng", "given": "Shuxia" } }, { "id": "Kaiser-J-T", "name": { "family": "Kaiser", "given": "Jens T." }, "orcid": "0000-0002-5948-5212" }, { "id": "Shan-S-O", "name": { "family": "Shan", "given": "Shu-ou" }, "orcid": "0000-0002-6526-1733" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "The Mitochondrial Fission Receptor MiD51 Requires ADP as a Cofactor", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Elsevier Ltd.\n\nReceived: December 31, 2013; Revised: December 31, 2013\nAccepted: January 2, 2014; Published: February 6, 2014.\n\nSupplemental Information includes five figures and can be found with this article online at http://dx.doi.org/10.1016/j.str.2014.01.001.\n\nWe are grateful to Meera Rao for assistance with the GTPase assay and Alasdair McDowell for guidance with EM. We thank the Beckman Foundation at Caltech for support of the EM resource and the Gordon and Betty Moore Foundation and Augoron Institute for support of the Grant Jensen lab microscopy center. We acknowledge the Gordon and Betty Moore Foundation, the Beckman Institute, and the Sanofi-Aventis Bioengineering Research Program at Caltech for their generous support of the Molecular Observatory at Caltech. Operations at SSRL are supported by the US Department of Energy and the National Institutes of Health (NIH). This work was supported by a grant from the NIH (GM062967). O.C.L. was supported by an R. L. Kirschstein National Research Service Award (5F31GM089327) and an American Physiological Society William Townsend Porter predoctoral fellowship. \n\nPDB Accession Numbers: 4OAF (native structure), 4OAG (bound to ADP), 4OAH (H201A mutant structure), 4OAI (dimer mutant structure)\n\nAccepted Version - nihms576282.pdf
Supplemental Material - mmc1.pdf
", "abstract": "Mitochondrial fission requires recruitment of dynamin-\nrelated protein 1 (Drp1) to the mitochondrial surface\nand activation of its GTP-dependent scission\nfunction. The Drp1 receptors MiD49 and MiD51 recruit\nDrp1 to facilitate mitochondrial fission, but their\nmechanism of action is poorly understood. Using\nX-ray crystallography, we demonstrate that MiD51\ncontains a nucleotidyl transferase domain that binds\nADP with high affinity. MiD51 recruits Drp1 via a surface\nloop that functions independently of ADP binding.\nHowever, in the absence of nucleotide binding,\nthe recruited Drp1 cannot be activated for fission.\nPurified MiD51 strongly inhibits Drp1 assembly\nand GTP hydrolysis in the absence of ADP. Addition\nof ADP relieves this inhibition and promotes Drp1\nassembly into spirals with enhanced GTP hydrolysis.\nOur results reveal ADP as an essential cofactor for\nMiD51 during mitochondrial fission.", "date": "2014-03-04", "date_type": "published", "publication": "Structure", "volume": "22", "number": "3", "publisher": "Cell Press", "pagerange": "367-377", "id_number": "CaltechAUTHORS:20140214-120458864", "issn": "0969-2126", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140214-120458864", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Gordon and Betty Moore Foundation" }, { "agency": "Caltech Beckman Institute" }, { "agency": "Caltech Sanofi-Aventis Bioengineering Research Program" }, { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5F31GM089327" }, { "agency": "American Physiological Society William Townsend Porter Predoctoral Fellowship" } ] }, "doi": "10.1016/j.str.2014.01.001", "pmcid": "PMC4066849", "primary_object": { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/vfbc2-1p098/files/mmc1.pdf" }, "related_objects": [ { "basename": "nihms576282.pdf", "url": "https://authors.library.caltech.edu/records/vfbc2-1p098/files/nihms576282.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Los\u00f3n, Oliver C.; Liu, Raymond; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/nshnr-eh480", "eprint_id": 44351, "eprint_status": "archive", "datestamp": "2023-08-19 23:36:27", "lastmod": "2023-10-26 00:24:55", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Samant-S-A", "name": { "family": "Samant", "given": "Sadhana A." } }, { "id": "Zhang-Hannah-J", "name": { "family": "Zhang", "given": "Hannah J." } }, { "id": "Hong-Zhigang", "name": { "family": "Hong", "given": "Zhigang" } }, { "id": "Pillai-V-B", "name": { "family": "Pillai", "given": "Vinodkumar B." } }, { "id": "Sundaresan-N-R", "name": { "family": "Sundaresan", "given": "Nagalingam R." } }, { "id": "Wolfgeher-D", "name": { "family": "Wolfgeher", "given": "Donald" } }, { "id": "Archer-S-L", "name": { "family": "Archer", "given": "Stephen L." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Gupta-M-P", "name": { "family": "Gupta", "given": "Mahesh P." } } ] }, "title": "SIRT3 Deacetylates and Activates OPA1 To Regulate Mitochondrial Dynamics during Stress", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 American Society for Microbiology.\n\nReceived 6 November 2013; accepted 6 December 2013 published ahead of print 16 December 2013.\n\nThis study was supported by the NIH-RO1 grants HL83423, HL117041, and HL111455 to M.P.G. We thank F. W. Alt and Christopher Rhodes for providing SIRT3KO and db/db mice, respectively. We are thankful to Marcia Haigis for providing\nSIRT3 WT and KO immortalized MEFs. We express gratitude to\nPaul Schumacker, Daniel Linseman, and Eric Verdin for providing the DNA vectors mentioned in Materials and Methods. We also thank Vytas Bindokas, Christine Labno, Shirley Bond, and Yimei Chen for the technical\nhelp in microscopy work.\n\nPublished - Mol._Cell._Biol.-2014-Samant-807-19.pdf
Supplemental Material - zmb999100314so1.pdf
", "abstract": "Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. There is significant evidence suggesting a stringent association between morphology and bioenergetics of mitochondria. Morphological alterations in mitochondria are linked to several pathological disorders, including cardiovascular diseases. The consequences of stress-induced acetylation of mitochondrial proteins on the organelle morphology remain largely unexplored. Here we report that OPA1, a mitochondrial fusion protein, was hyperacetylated in hearts under pathological stress and this posttranslational modification reduced the GTPase activity of the protein. The mitochondrial deacetylase SIRT3 was capable of deacetylating OPA1 and elevating its GTPase activity. Mass spectrometry and mutagenesis analyses indicated that in SIRT3-deficient cells OPA1 was acetylated at lysine 926 and 931 residues. Overexpression of a deacetylation-mimetic version of OPA1 recovered the mitochondrial functions of OPA1-null cells, thus demonstrating the functional significance of K926/931 acetylation in regulating OPA1 activity. Moreover, SIRT3-dependent activation of OPA1 contributed to the preservation of mitochondrial networking and protection of cardiomyocytes from doxorubicin-mediated cell death. In summary, these data indicated that SIRT3 promotes mitochondrial function not only by regulating activity of metabolic enzymes, as previously reported, but also by regulating mitochondrial dynamics by targeting OPA1.", "date": "2014-03", "date_type": "published", "publication": "Molecular and Cellular Biology", "volume": "34", "number": "5", "publisher": "American Society for Microbiology", "pagerange": "807-819", "id_number": "CaltechAUTHORS:20140317-111654355", "issn": "0270-7306", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140317-111654355", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "RO1-HL83423" }, { "agency": "NIH", "grant_number": "RO1-HL117041" }, { "agency": "NIH", "grant_number": "RO1-HL111455" } ] }, "doi": "10.1128/MCB.01483-13", "pmcid": "PMC4023816", "primary_object": { "basename": "Mol._Cell._Biol.-2014-Samant-807-19.pdf", "url": "https://authors.library.caltech.edu/records/nshnr-eh480/files/Mol._Cell._Biol.-2014-Samant-807-19.pdf" }, "related_objects": [ { "basename": "zmb999100314so1.pdf", "url": "https://authors.library.caltech.edu/records/nshnr-eh480/files/zmb999100314so1.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Samant, Sadhana A.; Zhang, Hannah J.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/1g3gw-tgy62", "eprint_id": 44054, "eprint_status": "archive", "datestamp": "2023-08-19 23:10:58", "lastmod": "2023-10-26 00:09:00", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Marinov-G-K", "name": { "family": "Marinov", "given": "Georgi K." }, "orcid": "0000-0003-1822-7273" }, { "id": "Wang-Yun-E", "name": { "family": "Wang", "given": "Yun E." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" }, { "id": "Wold-B-J", "name": { "family": "Wold", "given": "Barbara J." }, "orcid": "0000-0003-3235-8130" } ] }, "title": "Evidence for Site-Specific Occupancy of the Mitochondrial Genome by Nuclear Transcription Factors", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Marinov et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\nReceived August 20, 2013; Accepted November 18, 2013; Published January 20, 2014.\n\n\nFunding: This study has been supported by the Beckman Institute Functional Genomics Center, the Donald Bren Endowment, and NIH grants U54 HG004576,\nU54 HG006998, and GM062967. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nThe authors thank Henry Amrhein, Diane Trout, Sean Upchurch and Sreeram Balasubramanian for technical and computational assistance. \n\nAuthor Contributions:\nConceived and designed the experiments: GKM YEW BJW. Performed the experiments: GKM YEW. Analyzed the data: GKM YEW. Wrote the paper: GKM YEW DC BJW.\n\nPublished - journal.pone.0084713.pdf
Supplemental Material - journal.pone.0084713.s001.pdf
", "abstract": "Mitochondria contain their own circular genome, with mitochondria-specific transcription and replication systems and corresponding regulatory proteins. All of these proteins are encoded in the nuclear genome and are post-translationally imported into mitochondria. In addition, several nuclear transcription factors have been reported to act in mitochondria, but there has been no comprehensive mapping of their occupancy patterns and it is not clear how many other factors may also be found in mitochondria. Here we address these questions by using ChIP-seq data from the ENCODE, mouseENCODE and modENCODE consortia for 151 human, 31 mouse and 35 C. elegans factors. We identified 8 human and 3 mouse transcription factors with strong localized enrichment over the mitochondrial genome that was usually associated with the corresponding recognition sequence motif. Notably, these sites of occupancy are often the sites with highest ChIP-seq signal intensity within both the nuclear and mitochondrial genomes and are thus best explained as true binding events to mitochondrial DNA, which exist in high copy number in each cell. We corroborated these findings by immunocytochemical staining evidence for mitochondrial localization. However, we were unable to find clear evidence for mitochondrial binding in ENCODE and other publicly available ChIP-seq data for most factors previously reported to localize there. As the first global analysis of nuclear transcription factors binding in mitochondria, this work opens the door to future studies that probe the functional significance of the phenomenon.", "date": "2014-01-20", "date_type": "published", "publication": "PLoS ONE", "volume": "9", "number": "1", "publisher": "Public Library of Science", "pagerange": "Art. No. e84713", "id_number": "CaltechAUTHORS:20140228-100446267", "issn": "1932-6203", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140228-100446267", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Caltech Beckman Institute" }, { "agency": "Donald Bren Endowment" }, { "agency": "NIH", "grant_number": "U54 HG004576" }, { "agency": "NIH", "grant_number": "U54 HG006998" }, { "agency": "NIH", "grant_number": "GM062967" } ] }, "doi": "10.1371/journal.pone.0084713", "pmcid": "PMC3896368", "primary_object": { "basename": "journal.pone.0084713.pdf", "url": "https://authors.library.caltech.edu/records/1g3gw-tgy62/files/journal.pone.0084713.pdf" }, "related_objects": [ { "basename": "journal.pone.0084713.s001.pdf", "url": "https://authors.library.caltech.edu/records/1g3gw-tgy62/files/journal.pone.0084713.s001.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Marinov, Georgi K.; Wang, Yun E.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/91kpj-znn93", "eprint_id": 44529, "eprint_status": "archive", "datestamp": "2023-08-19 22:55:09", "lastmod": "2023-10-26 14:22:22", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ngo-Huu-B", "name": { "family": "Ngo", "given": "Huu B." } }, { "id": "Lovely-G-A", "name": { "family": "Lovely", "given": "Geoffrey A." } }, { "id": "Phillips-R", "name": { "family": "Phillips", "given": "Rob" }, "orcid": "0000-0003-3082-2809" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Macmillan Publishers Limited. Received 31 Jul 2013. Accepted 6 Dec 2013. Published 17 Jan 2014. We are grateful to the Gordon and Betty Moore Foundation and the Sanofi-Aventis Bioengineering Research Program at Caltech for their generous support of the Molecular Observatory at Caltech. Portions of this research were carried out at the Stanford Synchrotron Radiation Lightsource, supported by the US NIH and DOE. We thank Shou-ou Shan (California Institute of Technology) for use of equipment and insightful discussions, and Jens T. Kaiser for helpful discussions about structure determination. This work\nwas supported by NIH grants RO1 GM062967 (D.C.C.), DP1 OD000217A (Directors Pioneer Award, R.P.) and R01 GM085286 (R.P.).\n\nAccepted Version - nihms547300.pdf
Supplemental Material - ncomms4077-s1.pdf
", "abstract": "TFAM (transcription factor A, mitochondrial) is a DNA-binding protein that activates transcription at the two major promoters of mitochondrial DNA (mtDNA)\u2014the light strand promoter (LSP) and the heavy strand promoter 1 (HSP1). Equally important, it coats and packages the mitochondrial genome. TFAM has been shown to impose a U-turn on LSP DNA; however, whether this distortion is relevant at other sites is unknown. Here we present crystal structures of TFAM bound to HSP1 and to nonspecific DNA. In both, TFAM similarly distorts the DNA into a U-turn. Yet, TFAM binds to HSP1 in the opposite orientation from LSP explaining why transcription from LSP requires DNA bending, whereas transcription at HSP1 does not. Moreover, the crystal structures reveal dimerization of DNA-bound TFAM. This dimerization is dispensable for DNA bending and transcriptional activation but is important in DNA compaction. We propose that TFAM dimerization enhances mitochondrial DNA compaction by promoting looping of the DNA.", "date": "2014-01", "date_type": "published", "publication": "Nature Communications", "volume": "5", "number": "1", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 3077", "id_number": "CaltechAUTHORS:20140326-113402727", "issn": "2041-1723", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140326-113402727", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Gordon and Betty Moore Foundation" }, { "agency": "Caltech Sanofi-Aventis Bioengineering Research Program" }, { "agency": "Caltech Molecular Observatory" }, { "agency": "Department of Energy (DOE)" }, { "agency": "NIH", "grant_number": "RO1 GM062967" }, { "agency": "NIH", "grant_number": "DP1 OD000217A" }, { "agency": "NIH", "grant_number": "R01 GM085286" } ] }, "doi": "10.1038/ncomms4077", "pmcid": "PMC3936014", "primary_object": { "basename": "ncomms4077-s1.pdf", "url": "https://authors.library.caltech.edu/records/91kpj-znn93/files/ncomms4077-s1.pdf" }, "related_objects": [ { "basename": "nihms547300.pdf", "url": "https://authors.library.caltech.edu/records/91kpj-znn93/files/nihms547300.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Ngo, Huu B.; Lovely, Geoffrey A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/f8y1g-kkb63", "eprint_id": 52207, "eprint_status": "archive", "datestamp": "2023-08-22 11:12:17", "lastmod": "2024-01-13 16:12:43", "type": "book_section", "metadata_visibility": "show", "creators": { "items": [ { "id": "Pham-A-H", "name": { "family": "Pham", "given": "Anh H." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Analyzing Mitochondrial Dynamics in Mouse Organotypic Slice Cultures", "ispublished": "unpub", "full_text_status": "restricted", "keywords": "Organotypic cultures; Mitochondrial dynamics; Basal ganglia parasagittal cultures; Cerebellar slice cultures; Kymographs; Live imaging of mitochondria", "note": "\u00a9 2014 Elsevier Inc.", "abstract": "Mitochondria are mobile organelles that dynamically remodel their membranes and actively migrate along cytoskeletal tracks. There is overwhelming evidence that regulators of mitochondrial dynamics are critical for the survival and function of neural tissues. In multiple animal models, ablation of genes regulating mitochondrial shape result in stunted neural development and neurodegeneration. Organotypic cultures serve as ideal in vitro tissue models to further dissect the mechanisms of mitochondrial function in neuronal survival. Slice cultures preserve the three-dimensional cytoarchitecture of neural networks and can survive for prolonged periods in culture. In addition, these cultures allow long-term assessment of genetic or pharmacologic perturbations on neuronal function. Organotypic preparations from murine and rat models have been developed for many regions of the brain. In this chapter, we describe our methods for preparing basal ganglia and cerebellar slice cultures suitable for studying mitochondrial function in Parkinson's disease and cerebellar ataxia, respectively. With such slices, we describe a robust method for live imaging of mitochondrial dynamics. To quantitatively analyze mitochondrial motility, we show how to generate kymographs using the open source image analysis program ImageJ. These techniques provide a powerful platform for assessing mitochondrial activity in neural networks.", "date": "2014", "date_type": "published", "publisher": "Academic Press", "place_of_pub": "Amsterdam", "pagerange": "111-129", "id_number": "CaltechAUTHORS:20141201-094500370", "isbn": "9780128016152", "book_title": "Mitochondrial Function", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141201-094500370", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "contributors": { "items": [ { "id": "Murphy-A-N", "name": { "family": "Murphy", "given": "Anne N." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." } } ] }, "doi": "10.1016/B978-0-12-801415-8.00007-2", "resource_type": "book_section", "pub_year": "2014", "author_list": "Pham, Anh H. and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/sybea-02928", "eprint_id": 41867, "eprint_status": "archive", "datestamp": "2023-08-19 21:08:57", "lastmod": "2023-10-25 14:51:38", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wang-Yun-E", "name": { "family": "Wang", "given": "Yun E." } }, { "id": "Marinov-G-K", "name": { "family": "Marinov", "given": "Georgi K." }, "orcid": "0000-0003-1822-7273" }, { "id": "Wold-B-J", "name": { "family": "Wold", "given": "Barbara J." }, "orcid": "0000-0003-3235-8130" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Genome-Wide Analysis Reveals Coating of the Mitochondrial Genome by TFAM", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2013 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits\nunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\nReceived June 27, 2013; Accepted August 5, 2013; Published August 26, 2013.\n\nFunding: This work was supported by NIH grants GM062967 (DCC), U54 HG004576 (BJW), U54 HG006998 (BJW), the Beckman Foundation, and the\nDonald Bren Endowment. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nWe thank Igor Antoshechkin and the Millard and Muriel Jacobs\nGenetics and Genomics Laboratory for assistance with library\nbuilding and high-throughput sequencing. We thank Henry\nAmrhein and Diane Trout for computational assistance, Susan\nOu for monoclonal antibody production, and Elizabeth Nelson\nfor help with antibody characterization.\nAuthor Contributions:\nConceived and designed the experiments: YEW DCC.\nPerformed the experiments: YEW. Analyzed the data: YEW\nGKM. Wrote the manuscript: YEW GKM BJW DCC.\n\nPublished - journal.pone.0074513.pdf
Supplemental Material - journal.pone.0074513.s001.tif
", "abstract": "Mitochondria contain a 16.6 kb circular genome encoding 13 proteins as well as mitochondrial tRNAs and rRNAs. Copies of the genome are organized into nucleoids containing both DNA and proteins, including the machinery required for mtDNA replication and transcription. The transcription factor TFAM is critical for initiation of transcription and replication of the genome, and is also thought to perform a packaging function. Although specific binding sites required for initiation of transcription have been identified in the D-loop, little is known about the characteristics of TFAM binding in its nonspecific packaging state. In addition, it is unclear whether TFAM also plays a role in the regulation of nuclear gene expression. Here we investigate these questions by using ChIP-seq to directly localize TFAM binding to DNA in human cells. Our results demonstrate that TFAM uniformly coats the whole mitochondrial genome, with no evidence of robust TFAM binding to the nuclear genome. Our study represents the first high-resolution assessment of TFAM binding on a genome-wide scale in human cells.", "date": "2013-08-26", "date_type": "published", "publication": "PLoS ONE", "volume": "8", "number": "8", "publisher": "Public Library of Science", "pagerange": "Art. No. e74513", "id_number": "CaltechAUTHORS:20131010-110126087", "issn": "1932-6203", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20131010-110126087", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "NIH", "grant_number": "U54 HG004576" }, { "agency": "NIH", "grant_number": "U54 HG006998" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "Donald Bren Endowment" } ] }, "doi": "10.1371/journal.pone.0074513", "pmcid": "PMC3753274", "primary_object": { "basename": "journal.pone.0074513.pdf", "url": "https://authors.library.caltech.edu/records/sybea-02928/files/journal.pone.0074513.pdf" }, "related_objects": [ { "basename": "journal.pone.0074513.s001.tif", "url": "https://authors.library.caltech.edu/records/sybea-02928/files/journal.pone.0074513.s001.tif" } ], "resource_type": "article", "pub_year": "2013", "author_list": "Wang, Yun E.; Marinov, Georgi K.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/gkst3-g8g31", "eprint_id": 39309, "eprint_status": "archive", "datestamp": "2023-08-19 19:17:31", "lastmod": "2023-10-24 16:40:09", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Los\u00f3n-O-C", "name": { "family": "Los\u00f3n", "given": "Oliver Calvin" } }, { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Fis1, Mff, MiD49 and MiD51 facilitate Drp1 recruitment for mitochondrial fission", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2013 FASEB. This work was supported by the National Institutes of Health (GM062967). OCL was supported by a R. L. Kirschstein National Research Service Award (5F31GM089327).", "abstract": "Several mitochondrial outer membrane proteins\u2014Fis1, Mff, MiD49, and\nMiD51\u2014have been proposed to promote mitochondrial fission by recruiting the\ncytosolic GTPase Drp1, but fundamental issues remain concerning their function. A\nrecent study supported such a role for Mff, but not for Fis1. In addition, it is\nunclear whether MiD49 and MiD51 activate or inhibit fission because their\noverexpression causes extensive mitochondrial elongation. It is also unknown\nwhether these proteins can act in the absence of one another to mediate fission.\nUsing Fis1-null, Mff null, and Fis1/Mff -null cells, we show that both Fis1 and Mff\nhave roles in mitochondrial fission. We employ several independent, quantitative\ntechniques to show that these cell lines have significantly different mitochondrial\nelongation phenotypes. Using a specialized image analysis technique, we find that\nFis1 and Mff are important for regulating the number and size of Drp1 fluorescent\npuncta on mitochondria. Finally, we find that either MiD49 or MiD51 can mediate\nDrp1 recruitment and mitochondrial fission in the absence of Fis1 and Mff. We also\ndemonstrate that a significant enhancement of Drp1 phosphorylation at S637 is\ncausal for the elongation phenotype during MiD overexpression. These results\ndemonstrate that multiple receptors can recruit Drp1 to mediate mitochondrial\nfission, and suggest that these proteins may function in parallel pathways.", "date": "2013-04", "date_type": "published", "publication": "FASEB Journal", "volume": "27", "publisher": "Federation of American Societies for Experimental Biology", "pagerange": "Art. No. 582.2", "id_number": "CaltechAUTHORS:20130711-101356451", "issn": "0892-6638", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130711-101356451", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5F31GM089327" } ] }, "resource_type": "article", "pub_year": "2013", "author_list": "Los\u00f3n, Oliver Calvin; Chen, Hsiuchen; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/hkt5g-pe426", "eprint_id": 39495, "eprint_status": "archive", "datestamp": "2023-08-19 18:57:13", "lastmod": "2023-10-24 16:51:46", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Los\u00f3n-O-C", "name": { "family": "Los\u00f3n", "given": "Oliver C." } }, { "id": "Song-Zhiyin", "name": { "family": "Song", "given": "Zhiyin" } }, { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2013 Los\u00f3n et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution\u2013Noncommercial\u2013Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).\n\nReceived: Oct 9, 2012; Revised: Dec 13, 2012; Accepted: Dec 21, 2012.\nThis article was published online ahead of print in MBoC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E12-10-0721) on January 2, 2013.\n\nThis work was supported by the National Institutes of Health (GM062967). O.C.L. was supported by an R. L. Kirschstein National Research Service Award (5F31GM089327). The Drp1-null cells were a generous gift from Katsuyoshi Mihara (Kyushu University, Fukuoka, Japan).\n\nPublished - mbc.e12-10-0721.pdf
Supplemental Material - CombinedSupMats.pdf
", "abstract": "Several mitochondrial outer membrane proteins\u2014mitochondrial fission protein 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51, respectively)\u2014have been proposed to promote mitochondrial fission by recruiting the GTPase dynamin-related protein 1 (Drp1), but fundamental issues remain concerning their function. A recent study supported such a role for Mff but not for Fis1. In addition, it is unclear whether MiD49 and MiD51 activate or inhibit fission, because their overexpression causes extensive mitochondrial elongation. It is also unknown whether these proteins can act in the absence of one another to mediate fission. Using Fis1-null, Mff-null, and Fis1/Mff-null cells, we show that both Fis1 and Mff have roles in mitochondrial fission. Moreover, immunofluorescence analysis of Drp1 suggests that Fis1 and Mff are important for the number and size of Drp1 puncta on mitochondria. Finally, we find that either MiD49 or MiD51 can mediate Drp1 recruitment and mitochondrial fission in the absence of Fis1 and Mff. These results demonstrate that multiple receptors can recruit Drp1 to mediate mitochondrial fission.", "date": "2013-03-01", "date_type": "published", "publication": "Molecular Biology of the Cell", "volume": "24", "number": "5", "publisher": "American Society for Cell Biology", "pagerange": "659-667", "id_number": "CaltechAUTHORS:20130722-112639794", "issn": "1059-1524", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130722-112639794", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5F31GM089327" } ] }, "doi": "10.1091/mbc.E12-10-0721", "pmcid": "PMC3583668", "primary_object": { "basename": "CombinedSupMats.pdf", "url": "https://authors.library.caltech.edu/records/hkt5g-pe426/files/CombinedSupMats.pdf" }, "related_objects": [ { "basename": "mbc.e12-10-0721.pdf", "url": "https://authors.library.caltech.edu/records/hkt5g-pe426/files/mbc.e12-10-0721.pdf" } ], "resource_type": "article", "pub_year": "2013", "author_list": "Los\u00f3n, Oliver C.; Song, Zhiyin; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/rjjq4-pdd84", "eprint_id": 36992, "eprint_status": "archive", "datestamp": "2023-08-19 14:10:38", "lastmod": "2023-10-23 16:01:06", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kim-Kook-Hwan", "name": { "family": "Kim", "given": "Kook Hwan" } }, { "id": "Jeong-Yeo-Taek", "name": { "family": "Jeong", "given": "Yeon Taek" } }, { "id": "Oh-Hyunhee", "name": { "family": "Oh", "given": "Hyunhee" } }, { "id": "Kim-Seong-Hun", "name": { "family": "Kim", "given": "Seong Hun" } }, { "id": "Cho-Jae-Min", "name": { "family": "Cho", "given": "Jae Min" } }, { "id": "Kim-Yo-Na", "name": { "family": "Kim", "given": "Yo-Na" } }, { "id": "Kim-Su-Sung", "name": { "family": "Kim", "given": "Su Sung" } }, { "id": "Kim-Do-Hoon", "name": { "family": "Kim", "given": "Do Hoon" } }, { "id": "Hur-Kyu-Yeon", "name": { "family": "Hur", "given": "Kyu Yeon" } }, { "id": "Kim-Hyoung-Kyu", "name": { "family": "Kim", "given": "Hyoung Kyu" } }, { "id": "Ko-TaeHee", "name": { "family": "Ko", "given": "TaeHee" } }, { "id": "Han-Jin", "name": { "family": "Han", "given": "Jin" } }, { "id": "Kim-Hong-Lim", "name": { "family": "Kim", "given": "Hong Lim" } }, { "id": "Kim-Jin", "name": { "family": "Kim", "given": "Jin" } }, { "id": "Back-Sung-Hoon", "name": { "family": "Back", "given": "Sung Hoon" } }, { "id": "Komatsu-Masaaki", "name": { "family": "Komatsu", "given": "Masaaki" } }, { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Konishi-Morichika", "name": { "family": "Konishi", "given": "Morichika" } }, { "id": "Itoh-Nobuyuki", "name": { "family": "Itoh", "given": "Nobuyuki" } }, { "id": "Choi-Cheol-Soo", "name": { "family": "Choi", "given": "Cheol Soo" } }, { "id": "Lee-Myung-Shik", "name": { "family": "Lee", "given": "Myung-Shik" } } ] }, "title": "Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2012 Nature Publishing Group. Received 28 June; accepted 22 October; published online 2 December 2012. We thank S.R. Farmer (Boston University) for pGL3B-Fgf21 (\u22121370/+129), D. Ron (University of Cambridge) for Atf4-null MEFs, R.J. Kaufman (University of Michigan Medical Center) for Eif2aS/S and Eif2aA/A MEFs, S.J. Burden (New York University) for Mlc1f-Cre mice, N. Mizushima (Tokyo Medical and Dental University) for Tet-off Atg5-null MEFs, and H.W. Virgin for insightful comments on the manuscript. This study was supported by the Global Research Laboratory Grant of the National Research Foundation of Korea (K21004000003-10A0500-00310 to M.-S.L. and M. Komatsu) and the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Korea (A080967 to M.-S.L. and A102060 to C.S.C). M.-S.L. received the Bio R&D Program (2008-04090) and the Bio & Medical Technology Development Program grant from the Ministry of Education, Science & Technology, Korea (20110019335). \nAuthor Contributions: \nK.H.K., C.S.C. and M.-S.L. designed the study, analyzed data and wrote the manuscript. K.H.K. conducted all experiments except the portions indicated below, assisted by S.H.K., J.M.C., D.H.K. and K.Y.H. Y.T.J. analyzed the metabolic profiling of Atg7\u0394hep mice. H.O., Y.-N.K. and S.S.K. performed measurements of body composition, indirect calorimetry, the hyperinsulinemic-euglycemic clamp study and the fatty acid oxidation experiments. H.K.K., T.K. and J.H. measured the mitochondrial oxygen consumption. H.L.K. and J.K. performed the electron microscopy. S.H.B., M. Komatsu, H.C., D.C.C., M. Konishi and N.I. provided reagents, tissues, cells or mice and commented on the manuscript.\nCompeting Financial Interests: \nThe authors declare no competing financial interests.\n\nSupplemental Material - nm.3014-S1.pdf
", "abstract": "Despite growing interest and a recent surge in papers, the role of autophagy in glucose and lipid metabolism is unclear. We produced mice with skeletal muscle\u2013specific deletion of Atg7 (encoding autophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected from diet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acid oxidation and browning of white adipose tissue (WAT) owing to induction of fibroblast growth factor 21 (Fgf21). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf21 expression through induction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chain inhibitors also induced Fgf21 in an Atf4-dependent manner. We also observed induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a 'mitokine', and together these processes promote protection from diet-induced obesity and insulin resistance.", "date": "2013-01", "date_type": "published", "publication": "Nature Medicine", "volume": "19", "number": "1", "publisher": "Nature Publishing Group", "pagerange": "83-92", "id_number": "CaltechAUTHORS:20130219-151454535", "issn": "1078-8956", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130219-151454535", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Research Foundation of Korea Global Research Laboratory Grant", "grant_number": "K21004000003-10A0500-00310" }, { "agency": "Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs", "grant_number": "A080967" }, { "agency": "Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs", "grant_number": "A102060" }, { "agency": "Bio R&D Program", "grant_number": "2008-04090" }, { "agency": "Ministry of Education, Science & Technology, Korea, Bio & Medical Technology Development Program grant", "grant_number": "20110019335" } ] }, "doi": "10.1038/nm.3014", "primary_object": { "basename": "nm.3014-S1.pdf", "url": "https://authors.library.caltech.edu/records/rjjq4-pdd84/files/nm.3014-S1.pdf" }, "resource_type": "article", "pub_year": "2013", "author_list": "Kim, Kook Hwan; Jeong, Yeon Taek; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/5804v-m8438", "eprint_id": 35812, "eprint_status": "archive", "datestamp": "2023-08-19 13:29:53", "lastmod": "2023-10-20 21:11:25", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Pham-Anh-H", "name": { "family": "Pham", "given": "Anh H." } }, { "id": "Meng-Shuxia", "name": { "family": "Meng", "given": "Shuxia" } }, { "id": "Chu-Quynh-N", "name": { "family": "Chu", "given": "Quynh N." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Loss of Mfn2 results in progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2012 The Author. Published by Oxford University Press. \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/\nlicenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly\ncited.\nReceived July 20, 2012; Revised and Accepted July 24, 2012. \nFirst published online: July 31, 2012.\nWe thank Andrew D. Steele and Paul H. Patterson for use of\nequipment and software, Sally A. Kim for advice on organotypic slice cultures and Hsiuchen Chen for advice on mouse crosses. We are grateful to the Chan lab for discussion and comments on the manuscript. This work was supported by the National Institutes of Health (GM062967 to D.C.C.), Howard Hughes Medical Institute and the Thomas Hartman Foundation. Funding to pay the Open Access publication charges for this article was provided by\nthe Howard Hughes Medical Institute. Conflict of Interest statement. None declared.\n\nPublished - Hum._Mol._Genet.-2012-Pham-4817-26.pdf
Supplemental Material - dds311supp.pdf
Supplemental Material - dds311supp_video1.mov
Supplemental Material - dds311supp_video2.mov
Supplemental Material - dds311supp_video3.mov
", "abstract": "Mitochondria continually undergo fusion and fission, and these dynamic processes play a major role in regulating mitochondrial function. Studies of several genes associated with familial Parkinson's disease (PD) have implicated aberrant mitochondrial dynamics in the disease pathology, but the importance of these processes in dopaminergic neurons remains poorly understood. Because the mitofusins Mfn1 and Mfn2 are essential for mitochondrial fusion, we deleted these genes from a subset of dopaminergic neurons in mice. Loss of Mfn2 results in a movement defect characterized by reduced activity and rearing. In open field tests, Mfn2 mutants show severe, age-dependent motor deficits that can be rescued with L-3,4 dihydroxyphenylalanine. These motor deficits are preceded by the loss of dopaminergic terminals in the striatum. However, the loss of dopaminergic neurons in the midbrain occurs weeks after the onset of these motor and striatal deficits, suggesting a retrograde mode of neurodegeneration. In our conditional knockout strategy, we incorporated a mitochondrially targeted fluorescent reporter to facilitate tracking of mitochondria in the affected neurons. Using an organotypic slice culture system, we detected fragmented mitochondria in the soma and proximal processes of these neurons. In addition, we found markedly reduced mitochondrial mass and transport, which may contribute to the neuronal loss. These effects are specific for Mfn2, as the loss of Mfn1 yielded no corresponding defects in the nigrostriatal circuit. Our findings indicate that perturbations of mitochondrial dynamics can cause nigrostriatal defects and may be a risk factor for the neurodegeneration in PD.", "date": "2012-11-15", "date_type": "published", "publication": "Human Molecular Genetics", "volume": "21", "number": "22", "publisher": "Oxford University Press", "pagerange": "4817-4826", "id_number": "CaltechAUTHORS:20121205-091831236", "issn": "0964-6906", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121205-091831236", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "Thomas Hartman Foundation" } ] }, "doi": "10.1093/hmg/dds311", "pmcid": "PMC3607482", "primary_object": { "basename": "Hum._Mol._Genet.-2012-Pham-4817-26.pdf", "url": "https://authors.library.caltech.edu/records/5804v-m8438/files/Hum._Mol._Genet.-2012-Pham-4817-26.pdf" }, "related_objects": [ { "basename": "dds311supp.pdf", "url": "https://authors.library.caltech.edu/records/5804v-m8438/files/dds311supp.pdf" }, { "basename": "dds311supp_video1.mov", "url": "https://authors.library.caltech.edu/records/5804v-m8438/files/dds311supp_video1.mov" }, { "basename": "dds311supp_video2.mov", "url": "https://authors.library.caltech.edu/records/5804v-m8438/files/dds311supp_video2.mov" }, { "basename": "dds311supp_video3.mov", "url": "https://authors.library.caltech.edu/records/5804v-m8438/files/dds311supp_video3.mov" } ], "resource_type": "article", "pub_year": "2012", "author_list": "Pham, Anh H.; Meng, Shuxia; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/c0wk0-tkv23", "eprint_id": 36066, "eprint_status": "archive", "datestamp": "2023-09-22 22:37:41", "lastmod": "2023-10-23 23:25:15", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Pham-A-H", "name": { "family": "Pham", "given": "Anh H." } }, { "id": "McCaffery-J-M", "name": { "family": "McCaffery", "given": "J. Michael" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mouse lines with photo-activatable mitochondria to study mitochondrial dynamics", "ispublished": "pub", "full_text_status": "public", "keywords": "mitochondrial fusion; organelle trafficking; neurodegeneration; mouse model; Cre reporter", "note": "\u00a9 2012 Wiley Periodicals, Inc.\nReceived 10 May 2012; Revised 13 July 2012; Accepted 16 July 2012.\nArticle first published online: 11 Aug. 2012.\n\nContract grant sponsor: NIH; Contract grant number: GM062967.\nThe authors thank Shirley Pease for blastocyst injections.\nThey are grateful to Hsiuchen Chen for advice on\nanimal work. They appreciate the Chan lab members\nfor input on this manuscript.\n\nAccepted Version - nihms397060.pdf
", "abstract": "Many pathological states involve dysregulation of mitochondrial fusion, fission, or transport. These dynamic events are usually studied in cells lines because of the challenges in tracking mitochondria in tissues. To investigate mitochondrial dynamics in tissues and disease models, we generated two mouse lines withphoto-activatable mitochondria (PhAM). In the PhAM ^(floxed) line, a mitochondrially localized version of the photo-convertible fluorescent protein Dendra2 (mito-Dendra2) is targeted to the ubiquitously expressed Rosa26 locus, along with an upstream loxP-flanked termination signal. Expression of Cre in PhAM ^(floxed) cells results in bright mito-Dendra2 fluorescence without adverse effects on mitochondrial morphology. When crossed with Cre drivers, the PhAM ^(floxed) line expresses mito-Dendra2 in specific cell types, allowing mitochondria to be tracked even in tissues that have high cell density. In a second line (PhAM ^(excised)), the expression of mito-Dendra2 is ubiquitous, allowing mitochondria to be analyzed in a wide range of live and fixed tissues. By using photo-conversion techniques, we directly measured mitochondrial fusion events in cultured cells as well as tissues such as skeletal muscle. These mouse lines facilitate analysis of mitochondrial dynamics in a wide spectrum of primary cells and tissues, and can be used to examine mitochondria in developmental transitions and disease states.", "date": "2012-11", "date_type": "published", "publication": "Genesis", "volume": "50", "number": "11", "publisher": "Wiley", "pagerange": "833-843", "id_number": "CaltechAUTHORS:20121220-081335229", "issn": "1526-954X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121220-081335229", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" } ] }, "doi": "10.1002/dvg.22050", "pmcid": "PMC3508687", "primary_object": { "basename": "nihms397060.pdf", "url": "https://authors.library.caltech.edu/records/c0wk0-tkv23/files/nihms397060.pdf" }, "resource_type": "article", "pub_year": "2012", "author_list": "Pham, Anh H.; McCaffery, J. Michael; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/3bdjh-4hy29", "eprint_id": 33935, "eprint_status": "archive", "datestamp": "2023-08-19 12:24:48", "lastmod": "2023-10-18 21:38:36", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Fusion and Fission: Interlinked Processes Critical for Mitochondrial Health", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2012 Annual Reviews. Review in Advance first posted online\non August 29, 2012. I am grateful to Hsiuchen Chen for insightful comments on the manuscript. Work in my lab is supported by the Howard Hughes Medical Institute and the National Institutes of Health\n(GM062967 and GM083121).", "abstract": "Mitochondria are dynamic organelles that continually undergo fusion\nand fission. These opposing processes work in concert to maintain the\nshape, size, and number of mitochondria and their physiological function.\nSome of the major molecules mediating mitochondrial fusion and\nfission in mammals have been discovered, but the underlying molecular\nmechanisms are only partially unraveled. In particular, the cast\nof characters involved in mitochondrial fission needs to be clarified.\nBy enabling content mixing between mitochondria, fusion and fission\nserve to maintain a homogeneous and healthy mitochondrial population.\nMitochondrial dynamics has been linked to multiple mitochondrial\nfunctions, including mitochondrial DNA stability, respiratory capacity,\napoptosis, response to cellular stress, and mitophagy. Because of these\nimportant functions, mitochondrial fusion and fission are essential in\nmammals, and even mild defects in mitochondrial dynamics are associated\nwith disease. A better understanding of these processes likely will\nultimately lead to improvements in human health.", "date": "2012-08-29", "date_type": "published", "publication": "Annual Review of Genetics", "volume": "46", "publisher": "Annual Reviews", "pagerange": "265-287", "id_number": "CaltechAUTHORS:20120907-130054764", "issn": "0066-4197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120907-130054764", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "NIH", "grant_number": "GM083121" } ] }, "doi": "10.1146/annurev-genet-110410-132529", "resource_type": "article", "pub_year": "2012", "author_list": "Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/nbmqx-exb60", "eprint_id": 33930, "eprint_status": "archive", "datestamp": "2023-08-19 11:02:26", "lastmod": "2023-10-18 21:38:23", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Gautier-C-A", "name": { "family": "Gautier", "given": "Clemente A." } }, { "id": "Glaime-E", "name": { "family": "Glaime", "given": "Emilie" } }, { "id": "Caballero-E", "name": { "family": "Caballero", "given": "Erica" } }, { "id": "N\u00fa\u00f1ez-L", "name": { "family": "N\u00fa\u00f1ez", "given": "Luc\u00eda" } }, { "id": "Song-Zhiyin", "name": { "family": "Song", "given": "Zhiyin" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" }, { "id": "Villalobos-C", "name": { "family": "Villalobos", "given": "Carlos" } }, { "id": "Shen-Jie", "name": { "family": "Shen", "given": "Jie" } } ] }, "title": "Regulation of mitochondrial permeability transition pore by PINK1", "ispublished": "pub", "full_text_status": "public", "keywords": "Parkinson's disease, Mitochondrial respiration, Mitochondrial transmembrane potential, Mitochondrial\npermeability transition pore, Calcium", "note": "\u00a9 2012 Gautier et al.; licensee BioMed Central Ltd. \nThis is an Open Access article distributed under the terms of the Creative\nCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and\nreproduction in any medium, provided the original work is properly cited.\nReceived: 16 March 2012. Accepted: 25 May 2012. Published: 25 May 2012. We thank Hiroo Yamaguchi and other Shen lab members for discussions. This work was supported by a grant from the NINDS (R01 NS041779). Authors' contribution: CG and JS conceived and designed the study and wrote the manuscript. CG and EG carried out the experiments and obtained the data for Figures 1-9.\nLM, EC and CV participated in experimental design for Figure 9, and ZS and DC carried out the mitochondrial morphological analysis using the retroviral vectors mt-DsRed in Figure 8. All authors read and approved the final manuscript.\n\nPublished - 1750-1326-7-22.pdf
", "abstract": "Background:\nLoss-of-function mutations in PTEN-induced kinase 1 (PINK1) have been linked to familial Parkinson's disease, but the underlying pathogenic mechanism remains unclear. We previously reported that loss of PINK1 impairs mitochondrial respiratory activity in mouse brains.\nResults:\nIn this study, we investigate how loss of PINK1 impairs mitochondrial respiration using cultured primary fibroblasts and neurons. We found that intact mitochondria in PINK1\u2212/\u2212 cells recapitulate the respiratory defect in isolated mitochondria from PINK1\u2212/\u2212 mouse brains, suggesting that these PINK1\u2212/\u2212 cells are a valid experimental system to study the underlying mechanisms. Enzymatic activities of the electron transport system complexes are normal in PINK1\u2212/\u2212 cells, but mitochondrial transmembrane potential is reduced. Interestingly, the opening of the mitochondrial permeability transition pore (mPTP) is increased in PINK1\u2212/\u2212 cells, and this genotypic difference between PINK1\u2212/\u2212 and control cells is eliminated by agonists or inhibitors of the mPTP. Furthermore, inhibition of mPTP opening rescues the defects in transmembrane potential and respiration in PINK1\u2212/\u2212 cells. Consistent with our earlier findings in mouse brains, mitochondrial morphology is similar between PINK1\u2212/\u2212 and wild-type cells, indicating that the observed mitochondrial functional defects are not due to morphological changes. Following FCCP treatment, calcium increases in the cytosol are higher in PINK1\u2212/\u2212 compared to wild-type cells, suggesting that intra-mitochondrial calcium concentration is higher in the absence of PINK1.\nConclusions:\nOur findings show that loss of PINK1 causes selective increases in mPTP opening and mitochondrial calcium, and that the excessive mPTP opening may underlie the mitochondrial functional defects observed in PINK1\u2212/\u2212 cells.", "date": "2012-05-25", "date_type": "published", "publication": "Molecular Neurodegeneration", "volume": "7", "number": "1", "publisher": "BioMed Central", "pagerange": "Art. No. 22", "id_number": "CaltechAUTHORS:20120907-104242655", "issn": "1750-1326", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120907-104242655", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 NS041779" } ] }, "doi": "10.1186/1750-1326-7-22", "pmcid": "PMC3405481", "primary_object": { "basename": "1750-1326-7-22.pdf", "url": "https://authors.library.caltech.edu/records/nbmqx-exb60/files/1750-1326-7-22.pdf" }, "resource_type": "article", "pub_year": "2012", "author_list": "Gautier, Clemente A.; Glaime, Emilie; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/3bq5f-7z027", "eprint_id": 31604, "eprint_status": "archive", "datestamp": "2023-08-19 10:53:55", "lastmod": "2023-10-17 18:42:53", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-Jia", "name": { "family": "Li", "given": "Jia" } }, { "id": "Liu-Xiaolei", "name": { "family": "Liu", "given": "Xiaolei" } }, { "id": "Wang-Huayan", "name": { "family": "Wang", "given": "Huayan" } }, { "id": "Zhang-Weiping", "name": { "family": "Zhang", "given": "Weiping" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Shi-Yuguang", "name": { "family": "Shi", "given": "Yuguang" } } ] }, "title": "Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2012 National Academy of Sciences. Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute at Princess Margaret Hospital, University Health Network, Toronto, ON, Canada, and approved March 23, 2012 (received for review December 5, 2011). Published online before print April 16, 2012. We thank Mr. Roland Myers for EM analysis and Dr. Jaeseok Han for technical help with MEF isolation. This study was supported, in part, by National Institutes of Health Grants DK076685 (to Y.S.) and GM062967 (to D.C.C.) and a scholarship from the Chinese National Scholarship\nCouncil (to J.L.). Author contributions: Y.S. designed research; J.L. and X.L. performed research; H.W.,\nW.Z., and D.C.C. contributed new reagents/analytic tools; J.L., X.L., D.C.C., and Y.S. analyzed data; and J.L. and Y.S. wrote the paper.\n\nPublished - Li2012p18148P_Natl_Acad_Sci_Usa.pdf
Supplemental Material - pnas.201120043SI.pdf
", "abstract": "Oxidative stress causes mitochondrial fragmentation and dysfunction in age-related diseases through unknown mechanisms. Cardiolipin (CL) is a phospholipid required for mitochondrial oxidative phosphorylation. The function of CL is determined by its acyl composition, which is significantly altered by the onset of age-related diseases. Here, we examine a role of acyl-CoA:lysocardiolipin acyltransferase lysocardiolipin acyltransferase 1 (ALCAT1), a lysocardiolipin acyltransferase that catalyzes pathological CL remodeling, in mitochondrial biogenesis. We show that overexpression of ALCAT1 causes mitochondrial fragmentation through oxidative stress and depletion of mitofusin mitofusin 2 (MFN2) expression. Strikingly, ALCAT1 overexpression also leads to mtDNA instability and depletion that are reminiscent of MFN2 deficiency. Accordingly, expression of MFN2 completely rescues mitochondrial fusion defect and respiratory dysfunction. Furthermore, ablation of ALCAT1 prevents mitochondrial fragmentation from oxidative stress by up-regulating MFN2 expression, mtDNA copy number, and mtDNA fidelity. Together, these findings reveal an unexpected role of CL remodeling in mitochondrial biogenesis, linking oxidative stress by ALCAT1 to mitochondrial fusion defect.", "date": "2012-05-01", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "109", "number": "18", "publisher": "National Academy of Sciences", "pagerange": "6975-6890", "id_number": "CaltechAUTHORS:20120523-083401514", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120523-083401514", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "DK076685" }, { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "Chinese National Scholarship Council" } ] }, "doi": "10.1073/pnas.1120043109", "pmcid": "PMC3345005", "primary_object": { "basename": "Li2012p18148P_Natl_Acad_Sci_Usa.pdf", "url": "https://authors.library.caltech.edu/records/3bq5f-7z027/files/Li2012p18148P_Natl_Acad_Sci_Usa.pdf" }, "related_objects": [ { "basename": "pnas.201120043SI.pdf", "url": "https://authors.library.caltech.edu/records/3bq5f-7z027/files/pnas.201120043SI.pdf" } ], "resource_type": "article", "pub_year": "2012", "author_list": "Li, Jia; Liu, Xiaolei; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/p4kaw-z8w74", "eprint_id": 36074, "eprint_status": "archive", "datestamp": "2023-08-19 10:32:48", "lastmod": "2023-10-20 22:12:48", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David" }, "orcid": "0000-0002-0191-2154" }, { "id": "Ngo-Huu-B", "name": { "family": "Ngo", "given": "Huu B." } }, { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } } ] }, "title": "Dynamics of mitochondria and mitochondrial DNA", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2012 FASEB.", "abstract": "Mitochondria are dynamic organelles that fuse and divide. The study of mice lacking these dynamic processes has revealed physiological roles for mitochondrial dynamics. Recent studies indicate a link between mitochondrial dynamics and mitochondrial DNA (mtDNA) stability. To study this issue, we have performed structural studies on Tfam, a DNA binding protein that plays a central role in expression, maintenance, and organization of the mitochondrial genome. It activates transcription from mitochondrial promoters and organizes the mitochondrial genome into nucleoids. Using X-ray crystallography, we show that human Tfam forces promoter DNA to undergo a U-turn, reversing the direction of the DNA helix. The structural principles underlying DNA bending converge with those of the unrelated HU family proteins, which play analogous architectural roles in organizing bacterial nucleoids.", "date": "2012-04", "date_type": "published", "publication": "FASEB Journal", "volume": "26", "publisher": "Federation of American Societies for Experimental Biology", "pagerange": "Art. No. 103.2", "id_number": "CaltechAUTHORS:20121220-105846739", "issn": "0892-6638", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121220-105846739", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "resource_type": "article", "pub_year": "2012", "author_list": "Chan, David; Ngo, Huu B.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/2cbz0-ytt71", "eprint_id": 35419, "eprint_status": "archive", "datestamp": "2023-08-19 10:31:54", "lastmod": "2023-10-20 16:11:48", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Klionsky-D-J", "name": { "family": "Klionsky", "given": "Daniel J." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Guidelines for the use and interpretation of assays for monitoring autophagy", "ispublished": "pub", "full_text_status": "restricted", "keywords": "autolysosome, autophagosome, flux, LC3, lysosome, phagophore, stress, vacuole", "note": "\u00a9 2012 Landes Bioscience. Submitted: 01/26/12; Accepted: 01/26/12. In a rapidly expanding and highly dynamic field such as autophagy, it is possible that some authors who should have been included on this manuscript have been missed. D.J.K. extends his apologies to researchers in the field of autophagy\nwho, due to oversight or any other reason, could not be included. This work was supported by National Institutes of Health Public Health Service grant GM53396 to D.J.K. Due to space and other\nlimitations, it is not possible to include all other sources of financial support.", "abstract": "In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.", "date": "2012-04", "date_type": "published", "publication": "Autophagy", "volume": "8", "number": "4", "publisher": "Landes Bioscience", "pagerange": "445-544", "id_number": "CaltechAUTHORS:20121113-093943754", "issn": "1554-8627", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121113-093943754", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM53396" } ] }, "doi": "10.4161/auto.19496", "pmcid": "PMC3404883", "resource_type": "article", "pub_year": "2012", "author_list": "Klionsky, Daniel J. and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/ahxja-h6z77", "eprint_id": 30404, "eprint_status": "archive", "datestamp": "2023-08-19 10:21:42", "lastmod": "2023-10-17 15:42:17", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zhang-Yan", "name": { "family": "Zhang", "given": "Yan" } }, { "id": "Chan-Nickie-C", "name": { "family": "Chan", "given": "Nickie C." } }, { "id": "Ngo-Huu-B", "name": { "family": "Ngo", "given": "Huu B." } }, { "id": "Gristick-H-B", "name": { "family": "Gristick", "given": "Harry" }, "orcid": "0000-0002-1957-2821" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Crystal Structure of Mitochondrial Fission Complex Reveals Scaffolding Function for Mitochondrial Division 1 (Mdv1) Coiled Coil", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2012 by The American Society for Biochemistry and Molecular Biology, Inc. \n\nThis work was supported, in whole or in part, by National Institutes of Health Grants GM083121 and GM062967. \n\nThe atomic coordinates and structure factors (code 3UUX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/). Supported in part by a postdoctoral fellowship from the American Heart Association. \nWe thank Janet Shaw for yeast strains, constructs, and helpful discussions. Some of the initial screening was done at the Molecular Observatory at California Institute of Technology, which is supported by the Gordon and Betty Moore Foundation and the Sanofi-Aventis Bioengineering Research Program. Portions of this work were carried out at the Stanford Synchrotron Radiation Lightsource, a Directorate of the SLAC National Accelerator Laboratory and an Office of Science User Facility operated for the United States Department of Energy Office of Science by Stanford University. The Stanford Synchrotron Radiation Lightsource Structural Molecular Biology Program is supported by the Department of Energy Office of Biological and Environmental Research and\nby National Institutes of Health National Center for Research Resources Biomedical Technology Program Grant P41RR001209 and NIGMS.\n\nPublished - Zhang2012p17923J_Biol_Chem.pdf
Supplemental Material - jbc.M111.329359-1.pdf
", "abstract": "The mitochondrial fission machinery is best understood in the yeast Saccharomyces cerevisiae, where Fis1, Mdv1, and Dnm1 are essential components. Fis1 is a mitochondrial outer membrane protein that recruits the dynamin-related GTPase Dnm1 during the fission process. This recruitment occurs via Mdv1, which binds both Fis1 and Dnm1 and therefore functions as a molecular adaptor linking the two molecules. Mdv1 has a modular structure, consisting of an N-terminal extension that binds Fis1, a central coiled coil for dimerization, and a C-terminal WD40 repeat region that binds Dnm1. We have solved the crystal structure of a dimeric Mdv1-Fis1 complex that contains both the N-terminal extension and coiled-coil regions of Mdv1. Consistent with previous studies, Mdv1 binds Fis1 through a U-shaped helix-loop-helix motif, and dimerization of the Mdv1-Fis1 complex is mediated by the antiparallel coiled coil of Mdv1. However, the complex is surprisingly compact and rigid due to two additional contacts mediated by the surface of the Mdv1 coiled coil. The coiled coil packs against both Fis1 and the second helix of the Mdv1 helix-loop-helix motif. Mutational analyses showed that these contacts are important for mitochondrial fission activity. These results indicate that, in addition to dimerization, the unusually long Mdv1 coiled coil serves a scaffolding function to stabilize the Mdv1-Fis1 complex.", "date": "2012-03-23", "date_type": "published", "publication": "Journal of Biological Chemistry", "volume": "287", "number": "13", "publisher": "American Society for Biochemistry and Molecular Biology", "pagerange": "9855-9861", "id_number": "CaltechAUTHORS:20120501-070603033", "issn": "0021-9258", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120501-070603033", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM083121" }, { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "American Heart Association" }, { "agency": "Gordon and Betty Moore Foundation" }, { "agency": "Sanofi-Aventis Bioengineering Research Program" }, { "agency": "Department of Energy (DOE)" }, { "agency": "NIH", "grant_number": "P41RR001209" }, { "agency": "National Institute of General Medical Sciences" } ] }, "doi": "10.1074/jbc.M111.329359", "pmcid": "PMC3323041", "primary_object": { "basename": "Zhang2012p17923J_Biol_Chem.pdf", "url": "https://authors.library.caltech.edu/records/ahxja-h6z77/files/Zhang2012p17923J_Biol_Chem.pdf" }, "related_objects": [ { "basename": "jbc.M111.329359-1.pdf", "url": "https://authors.library.caltech.edu/records/ahxja-h6z77/files/jbc.M111.329359-1.pdf" } ], "resource_type": "article", "pub_year": "2012", "author_list": "Zhang, Yan; Chan, Nickie C.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/cd73r-fek55", "eprint_id": 30102, "eprint_status": "archive", "datestamp": "2023-08-19 10:16:38", "lastmod": "2023-10-17 15:22:35", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Schon-E-A", "name": { "family": "Schon", "given": "Eric A." } } ] }, "title": "Eliminating Mitochondrial DNA from Sperm", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2012 Elsevier Inc.\nAvailable online 12 March 2012.\n\nAccepted Version - nihms566809.pdf
", "abstract": "Most eukaryotes show uniparental inheritance of mitochondrial DNA (mtDNA). In this issue of Developmental Cell, DeLuca and O'Farrell (2012) show that active elimination of mtDNA during sperm development in Drosophila ensures that mature spermatozoa are devoid of DNA.", "date": "2012-03-13", "date_type": "published", "publication": "Developmental Cell", "volume": "22", "number": "3", "publisher": "Cell Press", "pagerange": "469-470", "id_number": "CaltechAUTHORS:20120416-130332825", "issn": "1534-5807", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120416-130332825", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.devcel.2012.02.008", "pmcid": "PMC3995028", "primary_object": { "basename": "nihms566809.pdf", "url": "https://authors.library.caltech.edu/records/cd73r-fek55/files/nihms566809.pdf" }, "resource_type": "article", "pub_year": "2012", "author_list": "Chan, David C. and Schon, Eric A." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/48ftw-1sa17", "eprint_id": 28246, "eprint_status": "archive", "datestamp": "2023-08-19 08:30:03", "lastmod": "2023-10-24 17:45:44", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ngo-Huu-B", "name": { "family": "Ngo", "given": "Huu B." } }, { "id": "Kaiser-J-T", "name": { "family": "Kaiser", "given": "Jens T." }, "orcid": "0000-0002-5948-5212" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2011 Nature Publishing Group.\n\nReceived 20 June 2011. Accepted 13 September 2011. Published online 30 October 2011. We thank N. Chan (California Institute of Technology) for making some mutant constructs, Y. Zhang and Z. Liu (California Institute of Technology) for suggestions on phase determination and structure refinement, T. Walton (California Institute of Technology) for advice on SEC-MALS, S. Shan (California Institute of Technology) for use of equipment and insightful discussions, the staff at the Stanford Synchrotron Radiation Lightsource (SSRL) for technical support with crystal screening and data collection, and members of the Chan laboratory for critical reading of the manuscript. We acknowledge the Gordon and Betty Moore Foundation for support of the Molecular Observatory at Caltech. SSRL is supported by the US Department of Energy and National Institutes of Health (NIH). This work was supported by NIH grants GM083121 (D.C.C.) and GM062967 (D.C.C.). \nAuthor Contributions: H.B.N. and D.C.C. designed the experiments, analyzed the data and wrote the paper. H.B.N. carried out the crystallography and performed the experimental work. J.T.K. helped with the crystallographic analysis.\n\nAccepted Version - nihms324801.pdf
", "abstract": "Tfam (transcription factor A, mitochondrial), a DNA-binding protein with tandem high-mobility group (HMG)-box domains, has a central role in the expression, maintenance and organization of the mitochondrial genome. It activates transcription from mitochondrial promoters and organizes the mitochondrial genome into nucleoids. Using X-ray crystallography, we show that human Tfam forces promoter DNA to undergo a U-turn, reversing the direction of the DNA helix. Each HMG-box domain wedges into the DNA minor groove to generate two kinks on one face of the DNA. On the opposite face, a positively charged \u03b1-helix serves as a platform to facilitate DNA bending. The structural principles underlying DNA bending converge with those of the unrelated HU family proteins, which have analogous architectural roles in organizing bacterial nucleoids. The functional importance of this extreme DNA bending is promoter specific and seems to be related to the orientation of Tfam on the promoters.", "date": "2011-11", "date_type": "published", "publication": "Nature Structural & Molecular Biology", "volume": "18", "number": "11", "publisher": "Nature Publishing Group", "pagerange": "1290-1296", "id_number": "CaltechAUTHORS:20111130-093715777", "issn": "1545-9985", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20111130-093715777", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Gordon and Betty Moore Foundation" }, { "agency": "Department of Energy (DOE)" }, { "agency": "NIH", "grant_number": "GM083121" }, { "agency": "NIH", "grant_number": "GM062967" } ] }, "doi": "10.1038/nsmb.2159", "pmcid": "PMC3210390", "primary_object": { "basename": "nihms324801.pdf", "url": "https://authors.library.caltech.edu/records/48ftw-1sa17/files/nihms324801.pdf" }, "resource_type": "article", "pub_year": "2011", "author_list": "Ngo, Huu B.; Kaiser, Jens T.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/dwxe5-tv940", "eprint_id": 24430, "eprint_status": "archive", "datestamp": "2023-08-22 03:01:46", "lastmod": "2023-10-23 22:42:21", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-Nickie-C", "name": { "family": "Chan", "given": "Nickie C." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Parkin uses the UPS to ship off dysfunctional mitochondria", "ispublished": "pub", "full_text_status": "public", "keywords": "Parkinson disease; parkin; ubiquitin-proteasome system; mitophagy; mitochondria", "note": "\u00a9 2011 Landes Bioscience.\nSubmitted: 03/05/11.\nRevised: 03/07/11.\nAccepted: 03/13/11.\n\nPublished - Chan2011p14817Autophagy.pdf
", "abstract": "Parkin is a ubiquitin E3 ligase that is implicated in familial Parkinson disease (PD). Previous studies have established its role in mitophagy, a pathway whereby dysfunctional mitochondria are targeted for autophagic degradation. We recently reported that a major function of Parkin in dysfunctional mitochondria is to activate the ubiquitin-proteasome system (UPS) for proteolysis of multiple outer membrane proteins, and that such activation of the UPS is a critical step in Parkin-mediated mitophagy. Here, we discuss the possible roles of the UPS in mitophagy and the pathogenesis of PD.", "date": "2011-07", "date_type": "published", "publication": "Autophagy", "volume": "7", "number": "7", "publisher": "Landes Bioscience", "pagerange": "771-772", "id_number": "CaltechAUTHORS:20110715-103712655", "issn": "1554-8627", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110715-103712655", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.4161/auto.7.7.15453", "pmcid": "PMC3973655", "primary_object": { "basename": "Chan2011p14817Autophagy.pdf", "url": "https://authors.library.caltech.edu/records/dwxe5-tv940/files/Chan2011p14817Autophagy.pdf" }, "resource_type": "article", "pub_year": "2011", "author_list": "Chan, Nickie C. and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/x7r9t-1tp91", "eprint_id": 23542, "eprint_status": "archive", "datestamp": "2023-08-19 06:18:56", "lastmod": "2023-10-23 19:44:31", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-Nickie-C", "name": { "family": "Chan", "given": "Nickie C." } }, { "id": "Salazar-A-M", "name": { "family": "Salazar", "given": "Anna M." } }, { "id": "Pham-Anh-H", "name": { "family": "Pham", "given": "Anh H." } }, { "id": "Sweredoski-M-J", "name": { "family": "Sweredoski", "given": "Michael J." }, "orcid": "0000-0003-0878-3831" }, { "id": "Kolawa-N-J", "name": { "family": "Kolawa", "given": "Natalie J." } }, { "id": "Graham-R-L-J", "name": { "family": "Graham", "given": "Robert L. J." } }, { "id": "Hess-S", "name": { "family": "Hess", "given": "Sonja" }, "orcid": "0000-0002-5904-9816" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2011 The Author. Published by Oxford University Press. Received January 27, 2011; Revised and Accepted February 1, 2011. First published online: February 4, 2011. \n\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/\nlicenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is\nproperly cited.\n\nWe thank Ray Deshaies and the Chan lab for critical discussions and reading of the manuscript. We are grateful to Drs Yu-Shin Sou and Masaaki Komatsu for providing the\nAtg3-null MEFs, and to Willem den Besten and Ray Deshaies\nfor providing ubiquitin plasmids. This work was supported by the National Institute of Health (GM062967) and the Thomas Hartman Foundation for Parkinson's Research. Funding to pay the Open Access publication charges for this article was provided by the Howard Hughes Medical Institute.\n\nPublished - Chan2011p13670Hum_Mol_Genet.pdf
Supplemental Material - ddr048supp.pdf
", "abstract": "Parkin, an E3 ubiquitin ligase implicated in Parkinson's disease, promotes degradation of dysfunctional mitochondria by autophagy. Using proteomic and cellular approaches, we show that upon translocation to mitochondria, Parkin activates the ubiquitin\u2013proteasome system (UPS) for widespread degradation of outer membrane proteins. This is evidenced by an increase in K48-linked polyubiquitin on mitochondria, recruitment of the 26S proteasome and rapid degradation of multiple outer membrane proteins. The degradation of proteins by the UPS occurs independently of the autophagy pathway, and inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in HeLa, SH-SY5Y and mouse cells. Although the mitofusins Mfn1 and Mfn2 are rapid degradation targets of Parkin, we find that degradation of additional targets is essential for mitophagy. These results indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates.", "date": "2011-05", "date_type": "published", "publication": "Human Molecular Genetics", "volume": "20", "number": "9", "publisher": "Oxford University Press", "pagerange": "1726-1737", "id_number": "CaltechAUTHORS:20110504-073756492", "issn": "0964-6906", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110504-073756492", "rights": "This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/\nlicenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is\nproperly cited.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "Thomas Hartman Foundation for Parkinson's Research" }, { "agency": "Howard Hughes Medical Institute (HHMI)" } ] }, "doi": "10.1093/hmg/ddr048", "pmcid": "PMC3071670", "primary_object": { "basename": "ddr048supp.pdf", "url": "https://authors.library.caltech.edu/records/x7r9t-1tp91/files/ddr048supp.pdf" }, "related_objects": [ { "basename": "Chan2011p13670Hum_Mol_Genet.pdf", "url": "https://authors.library.caltech.edu/records/x7r9t-1tp91/files/Chan2011p13670Hum_Mol_Genet.pdf" } ], "resource_type": "article", "pub_year": "2011", "author_list": "Chan, Nickie C.; Salazar, Anna M.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/fychn-7qe86", "eprint_id": 23363, "eprint_status": "archive", "datestamp": "2023-08-19 05:51:54", "lastmod": "2023-10-23 19:02:41", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Aravin-A-A", "name": { "family": "Aravin", "given": "Alexei A." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "piRNAs Meet Mitochondria", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2011 Elsevier Inc. Available online 14 March 2011.", "abstract": "zuc/MitoPLD encodes a conserved enzyme that localizes to mitochondria and hydrolyzes the mitochondria-specific lipid cardiolipin. Surprisingly, zuc/MitoPLD activity is required for Piwi-interacting RNA (piRNA)-mediated silencing of transposable elements in fly and mouse germlines, suggesting that signaling from mitochondria influences the piRNA pathway.", "date": "2011-03-15", "date_type": "published", "publication": "Developmental Cell", "volume": "20", "number": "3", "publisher": "Cell Press", "pagerange": "287-288", "id_number": "CaltechAUTHORS:20110418-113351861", "issn": "1534-5807", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110418-113351861", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.devcel.2011.03.003", "resource_type": "article", "pub_year": "2011", "author_list": "Aravin, Alexei A. and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/p1s8r-9kz10", "eprint_id": 22978, "eprint_status": "archive", "datestamp": "2023-08-22 00:17:04", "lastmod": "2023-10-23 17:46:53", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Physiological functions of mitochondrial fusion", "ispublished": "pub", "full_text_status": "restricted", "keywords": "mitochondrial fusion; mitofusin; OPA1; neurodegeneration", "note": "\u00a9 2010 New York Academy of Sciences.\nArticle first published online: 21 Jul. 2010.", "abstract": "In recent years, the dynamic nature of mitochondria has been discovered to be critical for their function. Here we discuss the molecular basis of mitochondrial fusion, its protective role in neurodegeneration, and its importance in cellular function. The mitofusins Mfn1 and Mfn2, GTPases localized to the outer membrane, mediate outer-membrane fusion. OPA1, a GTPase associated with the inner membrane, mediates subsequent inner-membrane fusion. Mutations in Mfn2 or OPA1 cause neurodegenerative diseases. Mouse models with defects in mitochondrial fusion genes have provided important avenues for understanding how fusion maintains mitochondrial physiology and neuronal function. Mitochondrial fusion enables content mixing within a mitochondrial population, thereby preventing permanent loss of essential components. Cells with reduced mitochondrial fusion, as a consequence, show a subpopulation of mitochondria that lack mtDNA nucleoids. Such mtDNA defects lead to respiration-deficient mitochondria, and their accumulation in neurons leads to impaired outgrowth of cellular processes and ultimately neurodegeneration.", "date": "2010-07", "date_type": "published", "publication": "Annals of the New York Academy of Sciences", "volume": "1201", "publisher": "New York Academy of Sciences", "pagerange": "21-25", "id_number": "CaltechAUTHORS:20110318-143103206", "issn": "0077-8923", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110318-143103206", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1111/j.1749-6632.2010.05615.x", "resource_type": "article", "pub_year": "2010", "author_list": "Chen, Hsiuchen and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/qvy2z-v5f50", "eprint_id": 18499, "eprint_status": "archive", "datestamp": "2023-08-19 02:45:45", "lastmod": "2023-10-20 16:27:26", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ban-Tadato", "name": { "family": "Ban", "given": "Tadato" } }, { "id": "Heymann-J-A-W", "name": { "family": "Heymann", "given": "J\u00fcrgen A. W." } }, { "id": "Song-Zhiyin", "name": { "family": "Song", "given": "Zhiyin" } }, { "id": "Hinshaw-J-E", "name": { "family": "Hinshaw", "given": "Jenny E." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 The Author 2010. Published by Oxford University Press. \n\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is\nproperly cited. \n\nReceived December 17, 2009; Revised February 15, 2010; Accepted February 22, 2010. \nWe thank Dr Kenichi Morigaki (Kobe University, Japan) for\nadvice on liposome preparation.\n\nThis work was supported by the National Institutes of Health\n(grant number GM062967 to D.C.C.) and the Intramural\nResearch Program of the National Institute of Diabetes and\nDigestive and Kidney Diseases (J.E.H.). T.B. was supported\nby the Japan Society for Promotion of Science (JSPS) with a\nPost-Doctoral Fellowship for Research Abroad. Funding to\npay the Open Access publication charges for this article was\nprovided by the Howard Hughes Medical Institute.\n\nPublished - Ban2010p10112Hum_Mol_Genet.pdf
Supplemental Material - ddq088_1.pdf
", "abstract": "The dynamin-related GTPase OPA1 is mutated in autosomal dominant optic atrophy (DOA) (Kjer type), an inherited neuropathy of the retinal ganglion cells. OPA1 is essential for the fusion of the inner mitochondrial membranes, but its mechanism of action remains poorly understood. Here we show that OPA1 has a low basal rate of GTP hydrolysis that is dramatically enhanced by association with liposomes containing negative phospholipids such as cardiolipin. Lipid association triggers assembly of OPA1 into higher order oligomers. In addition, we find that OPA1 can promote the protrusion of lipid tubules from the surface of cardiolipin-containing liposomes. In such lipid protrusions, OPA1 assemblies are observed on the outside of the lipid tubule surface, a protein-membrane topology similar to that of classical dynamins. The membrane tubulation activity of OPA1 is suppressed by GTP\u03b3S. OPA1 disease alleles associated with DOA display selective defects in several activities, including cardiolipin association, GTP hydrolysis and membrane tubulation. These findings indicate that interaction of OPA1 with membranes can stimulate higher order assembly, enhance GTP hydrolysis and lead to membrane deformation into tubules.", "date": "2010-06-01", "date_type": "published", "publication": "Human Molecular Genetics", "volume": "19", "number": "11", "publisher": "Oxford University Press", "pagerange": "2113-2122", "id_number": "CaltechAUTHORS:20100601-074205594", "issn": "0964-6906", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100601-074205594", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "National Institute of Diabetes and Digestive and Kidney Diseases" }, { "agency": "Japan Society for Promotion of Science (JSPS)" }, { "agency": "Howard Hughes Medical Institute (HHMI)" } ] }, "doi": "10.1093/hmg/ddq088", "pmcid": "PMC2865371", "primary_object": { "basename": "Ban2010p10112Hum_Mol_Genet.pdf", "url": "https://authors.library.caltech.edu/records/qvy2z-v5f50/files/Ban2010p10112Hum_Mol_Genet.pdf" }, "related_objects": [ { "basename": "ddq088_1.pdf", "url": "https://authors.library.caltech.edu/records/qvy2z-v5f50/files/ddq088_1.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Ban, Tadato; Heymann, J\u00fcrgen A. W.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/jzxk7-fzs15", "eprint_id": 18265, "eprint_status": "archive", "datestamp": "2023-08-21 23:46:29", "lastmod": "2023-10-20 15:55:13", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Vermulst-M", "name": { "family": "Vermulst", "given": "Marc" } }, { "id": "Wang-Yun-E", "name": { "family": "Wang", "given": "Yun E." } }, { "id": "Chomyn-A", "name": { "family": "Chomyn", "given": "Anne" } }, { "id": "Prolla-T-A", "name": { "family": "Prolla", "given": "Tomas A." } }, { "id": "McCaffery-J-M", "name": { "family": "McCaffery", "given": "J. Michael" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial Fusion Is Required for mtDNA Stability in Skeletal Muscle and Tolerance of mtDNA Mutations", "ispublished": "pub", "full_text_status": "public", "keywords": "CELLBIO; HUMDISEASE", "note": "\u00a9 2010 Elsevier Inc.\nReceived 23 July 2009; revised 13 December 2009; accepted 9 February 2010. Published: April 15, 2010. Available online 15 April 2010. \n\nWe thank Drs. S. Burden and P. Soriano for generously providing the MLC-Cre\nand Meox2-Cre mouse strains. We are grateful to Igor Antoshechkin, director\nof the Caltech Genomics Facility, for help with analysis of Solexa sequence\ndata. This work was supported by grants to D.C.C. (R01 grant GM062967\nand an Ellison Medical Foundation Senior Scholar Award) and J.M.M.\n(NCRR grant 1 S10 RR023454-01).\n\nAccepted Version - nihms200583.pdf
", "abstract": "Mitochondria are highly mobile and dynamic organelles that continually fuse and divide. These processes allow mitochondria to exchange contents, including mitochondrial DNA (mtDNA). Here we examine the functions of mitochondrial fusion in differentiated skeletal muscle through conditional deletion of the mitofusins Mfn1 and Mfn2, mitochondrial GTPases essential for fusion. Loss of the mitofusins causes severe mitochondrial dysfunction, compensatory mitochondrial proliferation, and muscle atrophy. Mutant mice have severe mtDNA depletion in muscle that precedes physiological abnormalities. Moreover, the mitochondrial genomes of the mutant muscle rapidly accumulate point mutations and deletions. In a related experiment, we find that disruption of mitochondrial fusion strongly increases mitochondrial dysfunction and lethality in a mouse model with high levels of mtDNA mutations. With its dual function in safeguarding mtDNA integrity and preserving mtDNA function in the face of mutations, mitochondrial fusion is likely to be a protective factor in human disorders associated with mtDNA mutations.", "date": "2010-04-16", "date_type": "published", "publication": "Cell", "volume": "141", "number": "2", "publisher": "Elsevier", "pagerange": "280-289", "id_number": "CaltechAUTHORS:20100512-141625107", "issn": "0092-8674", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100512-141625107", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Ellison Medical Foundation" }, { "agency": "National Center for Research Resources (NCRR)", "grant_number": "1 S10 RR023454-01" }, { "agency": "National Center for Research Resources (NCRR)", "grant_number": "R01 GM062967" } ] }, "doi": "10.1016/j.cell.2010.02.026", "pmcid": "PMC2876819", "primary_object": { "basename": "nihms200583.pdf", "url": "https://authors.library.caltech.edu/records/jzxk7-fzs15/files/nihms200583.pdf" }, "resource_type": "article", "pub_year": "2010", "author_list": "Chen, Hsiuchen; Vermulst, Marc; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/1e9cm-svq33", "eprint_id": 16830, "eprint_status": "archive", "datestamp": "2023-08-19 00:20:21", "lastmod": "2023-10-19 22:35:36", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-H", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial dynamics\u2013fusion, fission, movement, and mitophagy\u2013in neurodegenerative diseases", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2009 The Author(s). Received June 12, 2009; Revised June 12, 2009; Accepted July 16, 2009. \n\nWork in the authors' laboratory was supported by funds from\nNIH (GM062967 and GM083121), the Ellison Medical Foundation,\nand HHMI. Funding to pay the Open Access publication\ncharges for this article was provided by HHMI. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nPublished - Chen2009p6363Hum_Mol_Genet.pdf
", "abstract": "Neurons are metabolically active cells with high energy demands at locations distant from the cell body. As a result, these cells are particularly dependent on mitochondrial function, as reflected by the observation that diseases of mitochondrial dysfunction often have a neurodegenerative component. Recent discoveries have highlighted that neurons are reliant particularly on the dynamic properties of mitochondria. Mitochondria are dynamic organelles by several criteria. They engage in repeated cycles of fusion and fission, which serve to intermix the lipids and contents of a population of mitochondria. In addition, mitochondria are actively recruited to subcellular sites, such as the axonal and dendritic processes of neurons. Finally, the quality of a mitochondrial population is maintained through mitophagy, a form of autophagy in which defective mitochondria are selectively degraded. We review the general features of mitochondrial dynamics, incorporating recent findings on mitochondrial fusion, fission, transport and mitophagy. Defects in these key features are associated with neurodegenerative disease. Charcot-Marie-Tooth type 2A, a peripheral neuropathy, and dominant optic atrophy, an inherited optic neuropathy, result from a primary deficiency of mitochondrial fusion. Moreover, several major neurodegenerative diseases\u2014including Parkinson's, Alzheimer's and Huntington's disease\u2014involve disruption of mitochondrial dynamics. Remarkably, in several disease models, the manipulation of mitochondrial fusion or fission can partially rescue disease phenotypes. We review how mitochondrial dynamics is altered in these neurodegenerative diseases and discuss the reciprocal interactions between mitochondrial fusion, fission, transport and mitophagy.", "date": "2009-10-15", "date_type": "published", "publication": "Human Molecular Genetics", "volume": "18", "number": "2", "publisher": "Oxford University Press", "pagerange": "R169-R176", "id_number": "CaltechAUTHORS:20091130-112530331", "issn": "0964-6906", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20091130-112530331", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "NIH", "grant_number": "GM083121" }, { "agency": "Ellison Medical Foundation" }, { "agency": "Howard Hughes Medical Institute" } ] }, "collection": "CaltechAUTHORS", "doi": "10.1093/hmg/ddp326", "primary_object": { "basename": "Chen2009p6363Hum_Mol_Genet.pdf", "url": "https://authors.library.caltech.edu/records/1e9cm-svq33/files/Chen2009p6363Hum_Mol_Genet.pdf" }, "resource_type": "article", "pub_year": "2009", "author_list": "Chen, Hsiuchen and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/39d3n-d0m44", "eprint_id": 15100, "eprint_status": "archive", "datestamp": "2023-08-20 02:28:49", "lastmod": "2023-10-18 20:30:38", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Song-Zhiyin", "name": { "family": "Song", "given": "Zhiyin" } }, { "id": "Ghochani-M", "name": { "family": "Ghochani", "given": "Mariam" } }, { "id": "McCaffery-J-M", "name": { "family": "McCaffery", "given": "J. Michael" } }, { "id": "Frey-T-G", "name": { "family": "Frey", "given": "Terrence G." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitofusins and OPA1 Mediate Sequential Steps in Mitochondrial Membrane Fusion", "ispublished": "pub", "full_text_status": "public", "note": "Copyright \u00a9 2009 by The American Society for Cell Biology. Under the License and Publishing Agreement, authors grant to the general public, effective two months after publication of (i.e.,. the appearance of) the edited manuscript in an online issue of MBoC, the nonexclusive right to copy, distribute, or display the manuscript subject to the terms of the Creative Commons\u2013Noncommercial\u2013Share Alike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0). \n\nSubmitted March 30, 2009; Accepted May 18, 2009. Originally published as MBC in Press, 10.1091/mbc.E09-03-0252 on May 28, 2009. \n\nWe thank Dr. Steven Barlow for assistance with electron microscopy. We are grateful to Dr. Hsiuchen Chen (California Institute of Technology) for early work on this study and to Drs. Chen and Christiane Alexander (Max Delbr\u00fcck Center) for use of the OPA1-null cells. This work was supported by NIH grant GM062967 to D.C.C., and a Blasker Science and Technology Grant from the San Diego Foundation to T.G.F. Z.S. was supported by an Elizabeth Ross Fellowship.\n\nPublished - Song2009p5593Mol_Biol_Cell.pdf
Supplemental Material - 1.pdf
Supplemental Material - Smov1.mov
Supplemental Material - Smov2.mov
", "abstract": "Mitochondrial fusion requires the coordinated fusion of the outer and inner membranes. Three large GTPases\u2014OPA1 and the mitofusins Mfn1 and Mfn2\u2014are essential for the fusion of mammalian mitochondria. OPA1 is mutated in dominant optic atrophy, a neurodegenerative disease of the optic nerve. In yeast, the OPA1 ortholog Mgm1 is required for inner membrane fusion in vitro; nevertheless, yeast lacking Mgm1 show neither outer nor inner membrane fusion in vivo, because of the tight coupling between these two processes. We find that outer membrane fusion can be readily visualized in OPA1-null mouse cells in vivo, but these events do not progress to inner membrane fusion. Similar defects are found in cells lacking prohibitins, which are required for proper OPA1 processing. In contrast, double Mfn-null cells show neither outer nor inner membrane fusion. Mitochondria in OPA1-null cells often contain multiple matrix compartments bounded together by a single outer membrane, consistent with uncoupling of outer versus inner membrane fusion. In addition, unlike mitofusins and yeast Mgm1, OPA1 is not required on adjacent mitochondria to mediate membrane fusion. These results indicate that mammalian mitofusins and OPA1 mediate distinct sequential fusion steps that are readily uncoupled, in contrast to the situation in yeast.", "date": "2009-08-01", "date_type": "published", "publication": "Molecular Biology of the Cell", "volume": "20", "number": "15", "publisher": "American Society for Cell Biology", "pagerange": "3525-3532", "id_number": "CaltechAUTHORS:20090817-144815077", "issn": "1059-1524", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20090817-144815077", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "San Diego Foundation" }, { "agency": "Caltech" }, { "agency": "Howard Hughes Medical Institute (HHMI)" } ] }, "doi": "10.1091/mbc.E09-03-0252", "pmcid": "PMC2719570", "primary_object": { "basename": "1.pdf", "url": "https://authors.library.caltech.edu/records/39d3n-d0m44/files/1.pdf" }, "related_objects": [ { "basename": "Smov1.mov", "url": "https://authors.library.caltech.edu/records/39d3n-d0m44/files/Smov1.mov" }, { "basename": "Smov2.mov", "url": "https://authors.library.caltech.edu/records/39d3n-d0m44/files/Smov2.mov" }, { "basename": "Song2009p5593Mol_Biol_Cell.pdf", "url": "https://authors.library.caltech.edu/records/39d3n-d0m44/files/Song2009p5593Mol_Biol_Cell.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "Song, Zhiyin; Ghochani, Mariam; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/z7268-nmg50", "eprint_id": 15560, "eprint_status": "archive", "datestamp": "2023-08-21 21:36:44", "lastmod": "2023-10-19 14:34:44", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Tondera-D", "name": { "family": "Tondera", "given": "Daniel" } }, { "id": "Grandemange-S", "name": { "family": "Grandemange", "given": "Stephanie" } }, { "id": "Jourdain-A", "name": { "family": "Jourdain", "given": "Alexis" } }, { "id": "Karbowski-M", "name": { "family": "Karbowski", "given": "Mariusz" } }, { "id": "Mattenberger-Y", "name": { "family": "Mattenberger", "given": "Yves" } }, { "id": "Herzig-S", "name": { "family": "Herzig", "given": "Sebastien" } }, { "id": "Da-Cruz-S", "name": { "family": "Da Cruz", "given": "Sandrine" } }, { "id": "Clerc-P", "name": { "family": "Clerc", "given": "Pascaline" } }, { "id": "Raschke-I", "name": { "family": "Raschke", "given": "Ines" } }, { "id": "Merkwirth-C", "name": { "family": "Merkwirth", "given": "Carsten" } }, { "id": "Ehses-S", "name": { "family": "Ehses", "given": "Sarah" } }, { "id": "Krause-F", "name": { "family": "Krause", "given": "Frank" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Alexander-C", "name": { "family": "Alexander", "given": "Christiane" } }, { "id": "Bauer-C", "name": { "family": "Bauer", "given": "Christoph" } }, { "id": "Youle-R", "name": { "family": "Youle", "given": "Richard" } }, { "id": "Langer-T", "name": { "family": "Langer", "given": "Thomas" } }, { "id": "Martinou-J-C", "name": { "family": "Martinou", "given": "Jean-Claude" } } ] }, "title": "SLP-2 is required for stress-induced mitochondrial hyperfusion", "ispublished": "pub", "full_text_status": "restricted", "keywords": "ATP; fusion; mitochondria; stress; survival", "note": "\u00a9 2009 European Molecular Biology Organization.\nReceived: 24 November 2008; accepted: 12 March 2009; published\nonline: 9 April 2009.\nWe thank Dr Mihara and Dr Ishihara for rat OPA1-V1, OPA1-V1DS1,\nOPA1-V7, and AIF-OPA1-V7230\u2013997 cDNAs, Dr Scorrano for OPA1\ncDNA, Dr Rojo for human Mfn1 cDNA, Professor Wiesner for 143B\nrho0 cells, Professor Picard for pdtTomato-C1, Dr Dencher and Dr\nMadrenas for support, Dr Rossignol for his advices and all members\nof the lab for fruitful discussions. This work was funded by the\nDeutsche Forschungsgemeinschaft (DFG) (TO540/1-1), the NIH\nintramural program, the Swiss National Science Foundation (subsidy\n3100A0-109419/1), Oncosuisse Trust, Roche Research\nFoundation and the Geneva Department of Education. FK is funded\nin part by the European Union (MiMage, EC FP6 Contract No.\nLSHM-CT-2004-512020).", "abstract": "Mitochondria are dynamic organelles, the morphology of which results from an equilibrium between two opposing processes, fusion and fission. Mitochondrial fusion relies on dynamin-related GTPases, the mitofusins (MFN1 and 2) in the outer mitochondrial membrane and OPA1 (optic atrophy 1) in the inner mitochondrial membrane. Apart from a role in the maintenance of mitochondrial DNA, little is known about the physiological role of mitochondrial fusion. Here we report that mitochondria hyperfuse and form a highly interconnected network in cells exposed to selective stresses. This process precedes mitochondrial fission when it is triggered by apoptotic stimuli such as UV irradiation or actinomycin D. Stress-induced mitochondrial hyperfusion (SIMH) is independent of MFN2, BAX/BAK, and prohibitins, but requires L-OPA1, MFN1, and the mitochondrial inner membrane protein SLP-2. In the absence of SLP-2, L-OPA1 is lost and SIMH is prevented. SIMH is accompanied by increased mitochondrial ATP production and represents a novel adaptive pro-survival response against stress.", "date": "2009-06-03", "date_type": "published", "publication": "EMBO Journal", "volume": "28", "number": "11", "publisher": "European Molecular Biology Organization", "pagerange": "1589-1600", "id_number": "CaltechAUTHORS:20090903-083208055", "issn": "0261-4189", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20090903-083208055", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Deutsche Forschungsgemeinschaft (DFG)", "grant_number": "TO540/1-1" }, { "agency": "NIH" }, { "agency": "Swiss National Science Foundation", "grant_number": "3100A0-109419/1" }, { "agency": "Oncosuisse Trust" }, { "agency": "Roche Reasearch Foundation" }, { "agency": "Geneva Department of Education" }, { "agency": "European Union", "grant_number": "LSHM-CT-2004-512020" } ] }, "doi": "10.1038/emboj.2009.89", "pmcid": "PMC2693158", "resource_type": "article", "pub_year": "2009", "author_list": "Tondera, Daniel; Grandemange, Stephanie; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/x0nn0-cdj79", "eprint_id": 78886, "eprint_status": "archive", "datestamp": "2023-08-19 22:08:13", "lastmod": "2023-10-26 14:25:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Detmer-S-A", "name": { "family": "Detmer", "given": "Scott A." } }, { "id": "Vande-Velde-C", "name": { "family": "Vande Velde", "given": "Christine" } }, { "id": "Cleveland-D-W", "name": { "family": "Cleveland", "given": "Don W." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot\u2013Marie\u2013Tooth type 2A", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 The Author 2007. Published by Oxford University Press. \n\nReceived: 31 August 2007; Revision Received: 15 October 2007; Accepted: 22 October 2007; Published: 24 October 2007. \n\nWe thank Tim Miller, John Griffin and members of the Chan lab for helpful discussions; Tom Jessell for the HB9-EGFP mice and the HB9-IRES-EGFP cloning vector; Diane Solis and Gwen Williams for invaluable mouse support and Shirley Pease for directing pronuclear injections at the Caltech Transgenic and Knockout Core Facility. \n\nC.V.V. is funded by a Development Grant from the Muscular Dystrophy Association. D.W.C. receives salary support from the Ludwig Institute. This work was supported by NIH grant GM062967 to D.C.C. \n\nConflict of Interest statement. None declared.\n\nSupplemental Material - ddm314_Supplementary_Data.zip
", "abstract": "Charcot\u2013Marie\u2013Tooth (CMT) disease type 2A is a progressive, neurodegenerative disorder affecting long peripheral motor and sensory nerves. The most common clinical sign is weakness in the lower legs and feet, associated with muscle atrophy and gait defects. The axonopathy in CMT2A is caused by mutations in Mitofusin 2 (Mfn2), a mitochondrial GTPase necessary for the fusion of mitochondria. Most Mfn2 disease alleles dominantly aggregate mitochondria upon expression in cultured fibroblasts and neurons. To determine whether this property is related to neuronal pathogenesis, we used the HB9 promoter to drive expression of a pathogenic allele, Mfn2^(T105M), in the motor neurons of transgenic mice. Transgenic mice develop key clinical signs of CMT2A disease in a dosage-dependent manner. They have a severe gait defect due to an inability to dorsi-flex the hindpaws. Consequently, affected animals drag their hindpaws while walking and support themselves on the hind knuckles, rather than the soles. This distal muscle weakness is associated with reduced numbers of motor axons in the motor roots and severe reduction of the anterior calf muscles. Many motor neurons from affected animals show improper mitochondrial distribution, characterized by tight clusters of mitochondria within axons. This transgenic line recapitulates key motor features of CMT2A and provides a system to dissect the function of mitochondria in the axons of mammalian motor neurons.", "date": "2008-02-01", "date_type": "published", "publication": "Human Molecular Genetics", "volume": "17", "number": "3", "publisher": "Oxford University Press", "pagerange": "367-375", "id_number": "CaltechAUTHORS:20170710-085600164", "issn": "0964-6906", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170710-085600164", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Muscular Dystrophy Association" }, { "agency": "Ludwig Institute" }, { "agency": "NIH", "grant_number": "GM062967" } ] }, "doi": "10.1093/hmg/ddm314", "primary_object": { "basename": "ddm314_Supplementary_Data.zip", "url": "https://authors.library.caltech.edu/records/x0nn0-cdj79/files/ddm314_Supplementary_Data.zip" }, "resource_type": "article", "pub_year": "2008", "author_list": "Detmer, Scott A.; Vande Velde, Christine; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/8nc48-m5p70", "eprint_id": 11155, "eprint_status": "archive", "datestamp": "2023-08-22 10:28:34", "lastmod": "2023-10-16 23:18:49", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zhang-Yan", "name": { "family": "Zhang", "given": "Yan" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Structural basis for recruitment of mitochondrial fission complexes by Fis1", "ispublished": "pub", "full_text_status": "public", "keywords": "apoptosis; mitochondrial division; mitochondrial dynamics; tetratricopeptide repeat", "note": "\u00a92007 by the National Academy of Sciences. \n\nEdited by Giuseppe Attardi, California Institute of Technology, Pasadena, CA, and approved September 28, 2007 (received for review July 9, 2007). Published online before print November 12, 2007, doi: 10.1073/pnas.0706441104. This article is a PNAS Direct Submission. \n\nWe thank Dr. J. M. Shaw for providing the GFP\u2013Mdv1 vector, Priscilla Tee for technical assistance, and Erik Griffin (The Johns Hopkins University, Baltimore, MD) and Takumi Koshiba (Kyushu University, Fukuoka, Japan) for some expression constructs. Diffraction data were collected at the Stanford Synchrotron Radiation Laboratory. This work was supported by National Institutes of Health Grants GM062967 and GM083121 (to D.C.C.). Y.Z. was supported by an Elizabeth Ross postdoctoral fellowship. \n\nAuthor contributions: Y.Z. and D.C.C. designed research; Y.Z. performed research; Y.Z. and D.C.C. analyzed data; and Y.Z. and D.C.C. wrote the paper. \n\nThe authors declare no conflict of interest. \n\nData deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 2PQN and 2PQR). \n\nThis article contains supporting information online at www.pnas.org/cgi/content/full/0706441104/DC1.\n\nPublished - ZHApnas07.pdf
Published - ZHApnas07supfig5.pdf
", "abstract": "Mitochondrial fission controls mitochondrial shape and physiology, including mitochondrial remodeling in apoptosis. During assembly of the yeast mitochondrial fission complex, the outer membrane protein Fis1 recruits the dynamin-related GTPase Dnm1 to mitochondria. Fis1 contains a tetratricopeptide repeat (TPR) domain and interacts with Dnm1 via the molecular adaptors Mdv1 and Caf4. By using crystallographic analysis of adaptor-Fis1 complexes, we show that these adaptors use two helices to bind to both the concave and convex surfaces of the Fis1 TPR domain. Fis1 therefore contains two interaction interfaces, a binding mode that, to our knowledge, has not been observed previously for TPR domains. Genetic and biochemical studies indicate that both binding interfaces are important for binding of Mdv1 and Caf4 to Fis1 and for mitochondrial fission activity in vivo. Our results reveal how Fis1 recruits the mitochondrial fission complex and will facilitate efforts to manipulate mitochondrial fission.", "date": "2007-11-20", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "104", "number": "47", "publisher": "National Academy of Sciences", "pagerange": "18526-18530", "id_number": "CaltechAUTHORS:ZHApnas07", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:ZHApnas07", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "NSF", "grant_number": "GM083121" }, { "agency": "Elizabeth Ross postdoctoral fellowship" } ] }, "doi": "10.1073/pnas.0706441104", "pmcid": "PMC2141810", "primary_object": { "basename": "ZHApnas07.pdf", "url": "https://authors.library.caltech.edu/records/8nc48-m5p70/files/ZHApnas07.pdf" }, "related_objects": [ { "basename": "ZHApnas07supfig5.pdf", "url": "https://authors.library.caltech.edu/records/8nc48-m5p70/files/ZHApnas07supfig5.pdf" } ], "resource_type": "article", "pub_year": "2007", "author_list": "Zhang, Yan and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/g4bmy-whj87", "eprint_id": 55849, "eprint_status": "archive", "datestamp": "2023-08-19 21:21:59", "lastmod": "2023-10-20 23:18:15", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Detmer-S-A", "name": { "family": "Detmer", "given": "Scott A." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Functions and dysfunctions of mitochondrial dynamics", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2007 Nature Publishing Group.\n\nThis work was supported by grants from the National Institutes of Health. D.C.C. is an Ellison Medical Foundation Senior Scholar in Aging.", "abstract": "Recent findings have sparked renewed appreciation for the remarkably dynamic nature of mitochondria. These organelles constantly fuse and divide, and are actively transported to specific subcellular locations. These dynamic processes are essential for mammalian development, and defects lead to neurodegenerative disease. But what are the molecular mechanisms that control mitochondrial dynamics, and why are they important for mitochondrial function? We review these issues and explore how defects in mitochondrial dynamics might cause neuronal disease.", "date": "2007-11", "date_type": "published", "publication": "Nature Reviews. Molecular Cell Biology", "volume": "8", "number": "11", "publisher": "Nature Publishing Group", "pagerange": "870-879", "id_number": "CaltechAUTHORS:20150317-102457156", "issn": "1471-0072", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150317-102457156", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH" }, { "agency": "Ellison Medical Foundation" } ] }, "doi": "10.1038/nrm2275", "resource_type": "article", "pub_year": "2007", "author_list": "Detmer, Scott A. and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/dt6th-p1x27", "eprint_id": 8656, "eprint_status": "archive", "datestamp": "2023-08-22 09:48:34", "lastmod": "2023-10-16 21:37:57", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Song-Zhiyin", "name": { "family": "Song", "given": "Zhiyin" } }, { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Fiket-M", "name": { "family": "Fiket", "given": "Maja" } }, { "id": "Alexander-C", "name": { "family": "Alexander", "given": "Christiane" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2007 The Rockefeller University Press. \n\nSubmitted: 19 April 2007. Accepted: 25 July 2007. Published online 20 August 2007. \n\nWe thank Drs. Lorena Griparic and Alex van der Bliek for communicating results before publication and for providing the anti-OPA1 antibody. \n\nThis work was supported by National Institutes of Health grant GM062967 to D.C. Chan. Z. Song is supported by an Elizabeth Ross postdoctoral fellowship. \n\nFig. S1 shows that OPA1-null cells expressing a single OPA1 RNA splice form have extensive fusion activity in the PEG cell hybrid assay. Online supplemental material is available at http://www.jcb.org/cgi/content/full/jcb.200704110/DC1.\n\nPublished - SONjcb07.pdf
Supplemental Material - SONjcb07figS1.jpg
", "abstract": "OPA1, a dynamin-related guanosine triphosphatase mutated in dominant optic atrophy, is required for the fusion of mitochondria. Proteolytic cleavage by the mitochondrial processing peptidase generates long isoforms from eight messenger RNA (mRNA) splice forms, whereas further cleavages at protease sites S1 and S2 generate short forms. Using OPA1-null cells, we developed a cellular system to study how individual OPA1 splice forms function in mitochondrial fusion. Only mRNA splice forms that generate a long isoform in addition to one or more short isoforms support substantial mitochondrial fusion activity. On their own, long and short OPA1 isoforms have little activity, but, when coexpressed, they functionally complement each other. Loss of mitochondrial membrane potential destabilizes the long isoforms and enhances the cleavage of OPA1 at S1 but not S2. Cleavage at S2 is regulated by the i-AAA protease Yme1L. Our results suggest that mammalian cells have multiple pathways to control mitochondrial fusion through regulation of the spectrum of OPA1 isoforms.", "date": "2007-08-27", "date_type": "published", "publication": "Journal of Cell Biology", "volume": "178", "number": "5", "publisher": "Rockefeller University Press", "pagerange": "749-755", "id_number": "CaltechAUTHORS:SONjcb07", "issn": "0021-9525", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:SONjcb07", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" } ] }, "doi": "10.1083/jcb.200704110", "pmcid": "PMC2064540", "primary_object": { "basename": "SONjcb07.pdf", "url": "https://authors.library.caltech.edu/records/dt6th-p1x27/files/SONjcb07.pdf" }, "related_objects": [ { "basename": "SONjcb07figS1.jpg", "url": "https://authors.library.caltech.edu/records/dt6th-p1x27/files/SONjcb07figS1.jpg" }, { "basename": "medium.png", "url": "https://authors.library.caltech.edu/records/dt6th-p1x27/files/medium.png" }, { "basename": "small.png", "url": "https://authors.library.caltech.edu/records/dt6th-p1x27/files/small.png" } ], "resource_type": "article", "pub_year": "2007", "author_list": "Song, Zhiyin; Chen, Hsiuchen; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/8bd9h-k7916", "eprint_id": 78862, "eprint_status": "archive", "datestamp": "2023-08-22 09:44:37", "lastmod": "2023-10-26 14:24:28", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "McCaffery-J-M", "name": { "family": "McCaffery", "given": "J. Michael" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial Fusion Protects against Neurodegeneration in the Cerebellum", "ispublished": "pub", "full_text_status": "public", "keywords": "CELLBIO; HUMDISEASE; MOLNEURO", "note": "\u00a9 2007 Elsevier Inc. \n\nPublished: August 9, 2007. \n\nWe are grateful to Dr. M. E. Hatten for invaluable discussions about cerebellar development and Dr. T. Tomoda for helpful advice in experimental techniques. We thank Drs. S. Dymecki, H. Westphal, P. Soriano, A. McMahon, A. Joyner, and W. Wisden for their generous sharing of mouse strains. We thank S. Detmer for reviewing the manuscript. We appreciate D. Solis for her care of and keen observation of our animals. This work was supported by NIH grant GM062967 and the United Mitochondrial Disease Foundation.\n\nSupplemental Material - mmc1__1_.pdf
Supplemental Material - mmc2.mov
Supplemental Material - mmc3.mov
Supplemental Material - mmc4.mov
", "abstract": "Mutations in the mitochondrial fusion gene Mfn2 cause the human neurodegenerative disease Charcot-Marie-Tooth type 2A. However, the cellular basis underlying this relationship is poorly understood. By removing Mfn2 from the cerebellum, we established a model for neurodegeneration caused by loss of mitochondrial fusion. During development and after maturity, Purkinje cells require Mfn2 but not Mfn1 for dendritic outgrowth, spine formation, and cell survival. In vivo, cell culture, and electron microscopy studies indicate that mutant Purkinje cells have aberrant mitochondrial distribution, ultrastructure, and electron transport chain activity. In fibroblasts lacking mitochondrial fusion, the majority of mitochondria lack mitochondrial DNA nucleoids. This deficiency provides a molecular mechanism for the dependence of respiratory activity on mitochondrial fusion. Our results show that exchange of mitochondrial contents is important for mitochondrial function as well as organelle distribution in neurons and have important implications for understanding the mechanisms of neurodegeneration due to perturbations in mitochondrial fusion.", "date": "2007-08-10", "date_type": "published", "publication": "Cell", "volume": "130", "number": "3", "publisher": "Elsevier", "pagerange": "548-562", "id_number": "CaltechAUTHORS:20170707-132224024", "issn": "0092-8674", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170707-132224024", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "United Mitochondrial Disease Foundation" } ] }, "doi": "10.1016/j.cell.2007.06.026", "primary_object": { "basename": "mmc4.mov", "url": "https://authors.library.caltech.edu/records/8bd9h-k7916/files/mmc4.mov" }, "related_objects": [ { "basename": "mmc1__1_.pdf", "url": "https://authors.library.caltech.edu/records/8bd9h-k7916/files/mmc1__1_.pdf" }, { "basename": "mmc2.mov", "url": "https://authors.library.caltech.edu/records/8bd9h-k7916/files/mmc2.mov" }, { "basename": "mmc3.mov", "url": "https://authors.library.caltech.edu/records/8bd9h-k7916/files/mmc3.mov" } ], "resource_type": "article", "pub_year": "2007", "author_list": "Chen, Hsiuchen; McCaffery, J. Michael; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/j0xta-dpq46", "eprint_id": 78880, "eprint_status": "archive", "datestamp": "2023-08-19 20:05:11", "lastmod": "2023-10-26 14:25:35", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial Dynamics in Disease", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2007 Massachusetts Medical Society.", "abstract": "Mitochondria are subcellular organelles that coordinate numerous metabolic reactions, including those of the respiratory complexes that produce the ATP that powers cellular reactions. They have often been depicted as static, with a kidney-bean shape, but there is a growing appreciation of their dynamic nature. Moreover, they are strikingly varied in structure, ranging from small, spherical particles to long, interconnected filaments. Mitochondria are also highly motile and constantly move in a directed manner along cytoskeletal tracks within cells.", "date": "2007-04-26", "date_type": "published", "publication": "New England Journal of Medicine", "volume": "356", "number": "17", "publisher": "Massachusetts Medical Society", "pagerange": "1707-1709", "id_number": "CaltechAUTHORS:20170710-082833330", "issn": "0028-4793", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170710-082833330", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1056/NEJMp078040", "resource_type": "article", "pub_year": "2007", "author_list": "Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/0zx2f-9ew38", "eprint_id": 7637, "eprint_status": "archive", "datestamp": "2023-08-22 08:27:41", "lastmod": "2023-10-16 21:01:04", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Detmer-S-A", "name": { "family": "Detmer", "given": "Scott A." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 The Rockefeller University Press, 2007. \n\nSubmitted: 15 November 2006. Accepted: 16 January 2007. Published online 12 February 2007. \n\nWe are grateful to Hsiuchen Chen for helpful comments on the manuscript, members of the laboratory for encouragement, and the Beckman Imaging Center for use of confocal microscopes. \n\nThis work was supported by National Institutes of Health (NIH) grant GM062967. D.C. Chan was a Bren Scholar. S.A. Detmer was partially supported by NIH/National Research Service Award training grant 5T32GM07616. \n\nOnline supplemental material: Fig. S1 shows the mitochondrial profi les of MEFs expressing Mfn2 CMT2A alleles; this data is summarized in Fig. 1 C. Fig. S2 shows mitochondrial aggregation in MEFs highly overexpressing Mfn2 CMT2A alleles. Fig. S3 shows that at low infection rates, recombinant Mfn2 is present at approximately fourfold the level of endogenous Mfn2. Online supplemental material is available at http://www.jcb.org/cgi/content/full/jcb.200611080/DC1.\n\nPublished - DETjcb07.pdf
Supplemental Material - DETjcb07suppfig1.jpg
Supplemental Material - DETjcb07suppfig2.jpg
Supplemental Material - DETjcb07suppfig3.jpg
", "abstract": "Mfn2, an oligomeric mitochondrial protein important for mitochondrial fusion, is mutated in Charcot-Marie-Tooth disease (CMT) type 2A, a peripheral neuropathy characterized by axonal degeneration. In addition to homooligomeric complexes, Mfn2 also associates with Mfn1, but the functional significance of such heterooligomeric complexes is unknown. Also unknown is why Mfn2 mutations in CMT2A lead to cell type\u2013specific defects given the widespread expression of Mfn2. In this study, we show that homooligomeric complexes formed by many Mfn2 disease mutants are nonfunctional for mitochondrial fusion. However, wild-type Mfn1 complements mutant Mfn2 through the formation of heterooligomeric complexes, including complexes that form in trans between mitochondria. Wild-type Mfn2 cannot complement the disease alleles. Our results highlight the functional importance of Mfn1\u2013Mfn2 heterooligomeric complexes and the close interplay between the two mitofusins in the control of mitochondrial fusion. Furthermore, they suggest that tissues with low Mfn1 expression are vulnerable in CMT2A and that methods to increase Mfn1 expression in the peripheral nervous system would benefit CMT2A patients.", "date": "2007-02-12", "date_type": "published", "publication": "Journal of Cell Biology", "volume": "170", "number": "4", "publisher": "Rockefeller University Press", "pagerange": "405-414", "id_number": "CaltechAUTHORS:DETjcb07", "issn": "0021-9525", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:DETjcb07", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "Bren Scholar" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5T32GM07616" } ] }, "doi": "10.1083/jcb.200611080", "pmcid": "PMC2063976", "primary_object": { "basename": "small.png", "url": "https://authors.library.caltech.edu/records/0zx2f-9ew38/files/small.png" }, "related_objects": [ { "basename": "DETjcb07.pdf", "url": "https://authors.library.caltech.edu/records/0zx2f-9ew38/files/DETjcb07.pdf" }, { "basename": "DETjcb07suppfig1.jpg", "url": "https://authors.library.caltech.edu/records/0zx2f-9ew38/files/DETjcb07suppfig1.jpg" }, { "basename": "DETjcb07suppfig2.jpg", "url": "https://authors.library.caltech.edu/records/0zx2f-9ew38/files/DETjcb07suppfig2.jpg" }, { "basename": "DETjcb07suppfig3.jpg", "url": "https://authors.library.caltech.edu/records/0zx2f-9ew38/files/DETjcb07suppfig3.jpg" }, { "basename": "medium.png", "url": "https://authors.library.caltech.edu/records/0zx2f-9ew38/files/medium.png" } ], "resource_type": "article", "pub_year": "2007", "author_list": "Detmer, Scott A. and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/gj5y3-j0p73", "eprint_id": 56492, "eprint_status": "archive", "datestamp": "2023-08-19 18:48:02", "lastmod": "2023-10-23 15:29:08", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Choi-Seok-Yong", "name": { "family": "Choi", "given": "Seok-Yong" } }, { "id": "Huang-Ping", "name": { "family": "Huang", "given": "Ping" } }, { "id": "Jenkins-G-M", "name": { "family": "Jenkins", "given": "Gary M." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Schiller-J", "name": { "family": "Schiller", "given": "Juergen" } }, { "id": "Frohman-M-A", "name": { "family": "Frohman", "given": "Michael A." } } ] }, "title": "A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2006 Nature Publishing Group. Received 26 June 2006; accepted 10 August 2006; published online 8 October 2006.\n\nWe thank U. Moll, C. Kisker, J. C. Hsieh, G. Rodomen, S. Van Horn, M. Fuller, M. Rojo, R. J. Youle, D. Bogenhagen, J. Vicogne, A. Neiman, G. Du, S. Tsirka and members of the Frohman lab for technical advice and assistance, reagents\nand critical discussions. The work was supported by awards National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; 64166) and National Institute of General Medical Sciences (NIGMS; 71520) to M.A.F., a National\nResearch Service Award (NRSA) T32 fellowship to G.M.J., and a fellowship award to S.Y.C. from the United Mitochondrial Disease Foundation.\n\nSupplemental Material - ncb1487-s1.pdf
", "abstract": "Fusion of vesicles into target membranes during many types of regulated exocytosis requires both SNARE-complex proteins and fusogenic lipids, such as phosphatidic acid. Mitochondrial fusion is less well understood but distinct, as it is mediated instead by the protein Mitofusin (Mfn). Here, we identify an ancestral member of the phospholipase D (PLD) superfamily of lipid-modifying enzymes that is required for mitochondrial fusion. Mitochondrial PLD (MitoPLD) targets to the external face of mitochondria and promotes trans-mitochondrial membrane adherence in a Mfn-dependent manner by hydrolysing cardiolipin to generate phosphatidic acid. These findings reveal that although mitochondrial fusion and regulated exocytic fusion are mediated by distinct sets of protein machinery, the underlying processes are unexpectedly linked by the generation of a common fusogenic lipid. Moreover, our findings suggest a novel basis for the mitochondrial fragmentation observed during apoptosis.", "date": "2006-11", "date_type": "published", "publication": "Nature Cell Biology", "volume": "8", "number": "11", "publisher": "Nature Publishing Group", "pagerange": "1255-1262", "id_number": "CaltechAUTHORS:20150408-135021559", "issn": "1465-7392", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150408-135021559", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)", "grant_number": "64166" }, { "agency": "National Institute of General Medical Sciences (NIGMS)", "grant_number": "71520" }, { "agency": "NIH Predoctoral Fellowship" }, { "agency": "United Mitochondrial Disease Foundation" } ] }, "doi": "10.1038/ncb1487", "primary_object": { "basename": "ncb1487-s1.pdf", "url": "https://authors.library.caltech.edu/records/gj5y3-j0p73/files/ncb1487-s1.pdf" }, "resource_type": "article", "pub_year": "2006", "author_list": "Choi, Seok-Yong; Huang, Ping; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/7jjye-bx222", "eprint_id": 7638, "eprint_status": "archive", "datestamp": "2023-08-22 07:05:04", "lastmod": "2023-10-16 21:01:06", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial Fusion and Fission in Mammals", "ispublished": "pub", "full_text_status": "public", "keywords": "mitochondrial dynamics, organelle morphology, membrane fusion,\nmembrane trafficking", "note": "\u00a9 2006 by Annual Reviews. \n\nFirst published online as a Review in Advance on May 11, 2006. \n\nI am grateful to Hsiuchen Chen for helpful comments on the manuscript. Work in my laboratory is supported by the NIH (GM062967), the Muscular Dystrophy Association, and the United Mitochondrial Disease Foundation.\n\nPublished - CHAarcdb06.pdf
", "abstract": "Eukaryotic cells maintain the overall shape of their mitochondria by balancing the opposing processes of mitochondrial fusion and fission. Unbalanced fission leads to mitochondrial fragmentation, and unbalanced fusion leads to mitochondrial elongation. Moreover, these processes control not only the shape but also the function of mitochondria. Mitochondrial dynamics allows mitochondria to interact with each other; without such dynamics, the mitochondrial population consists of autonomous organelles that have impaired function. Key components of the mitochondrial fusion and fission machinery have been identified, allowing initial dissection of their mechanisms of action. These components play important roles in mitochondrial function and development as well as programmed cell death. Disruption of the fusion machinery leads to neurodegenerative disease.", "date": "2006-11", "date_type": "published", "publication": "Annual Review of Cell and Developmental Biology", "volume": "22", "publisher": "Annual Reviews", "pagerange": "79-99", "id_number": "CaltechAUTHORS:CHAarcdb06", "issn": "1081-0706", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHAarcdb06", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "Muscular Dystrophy Association" }, { "agency": "United Mitochondrial Disease Foundation" } ] }, "doi": "10.1146/annurev.cellbio.22.010305.104638", "primary_object": { "basename": "CHAarcdb06.pdf", "url": "https://authors.library.caltech.edu/records/7jjye-bx222/files/CHAarcdb06.pdf" }, "resource_type": "article", "pub_year": "2006", "author_list": "Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/cve2a-v8t76", "eprint_id": 78864, "eprint_status": "archive", "datestamp": "2023-08-19 18:23:01", "lastmod": "2023-10-26 14:24:37", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Critical dependence of neurons on mitochondrial dynamics", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2006 Elsevier Ltd. \n\nAvailable online 14 June 2006. \n\nWork in D. Chan's laboratory is funded by the NIH (GM062967), the Muscular Dystrophy Association, and the United Mitochondrial Disease Foundation. D. Chan is a Bren Scholar.", "abstract": "The selective disruption of certain cell types \u2014 notably neurons \u2014 in diseases involving mitochondrial dysfunction is thought to reflect the high-energy requirements of these cells, but few details are known. Recent studies have provided clues to the cellular basis of this mitochondrial requirement. Mitochondria are regionally organized within some nerve cells, with higher accumulations in the soma, the hillock, the nodes of Ranvier and the nerve terminal. In the synaptic region, mitochondria regulate calcium and ATP levels, thereby maintaining synaptic transmission and structure. Defects in mitochondrial dynamics can cause deficits in mitochondrial respiration, morphology and motility. Moreover, mutations in the mitochondrial fusion genes Mitofusin-2 and OPA1 lead to the peripheral neuropathy Charcot-Marie-Tooth type 2A and dominant optic atrophy. Perhaps it is the strict spatial and functional requirements for mitochondria in neurons that cause defects in mitochondrial fusion to manifest primarily as neurodegenerative diseases.", "date": "2006-08", "date_type": "published", "publication": "Current Opinion in Cell Biology", "volume": "18", "number": "4", "publisher": "Elsevier", "pagerange": "453-459", "id_number": "CaltechAUTHORS:20170707-134400692", "issn": "0955-0674", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170707-134400692", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "Muscular Dystrophy Association" }, { "agency": "United Mitochondrial Disease Foundation" }, { "agency": "Bren Foundation" } ] }, "doi": "10.1016/j.ceb.2006.06.004", "resource_type": "article", "pub_year": "2006", "author_list": "Chen, Hsiuchen and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/1g77s-adw62", "eprint_id": 78861, "eprint_status": "archive", "datestamp": "2023-08-19 18:07:49", "lastmod": "2023-10-26 14:24:22", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondria: Dynamic Organelles in Disease, Aging, and Development", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2006 Elsevier Inc. \n\nAvailable online 29 June 2006. \n\nI am grateful to Hsiuchen Chen for helpful discussions.\n\nSupplemental Material - 1-s2.0-S0092867406007689-mmc1.mov
", "abstract": "Mitochondria are the primary energy-generating system in most eukaryotic cells. Additionally, they participate in intermediary metabolism, calcium signaling, and apoptosis. Given these well-established functions, it might be expected that mitochondrial dysfunction would give rise to a simple and predictable set of defects in all tissues. However, mitochondrial dysfunction has pleiotropic effects in multicellular organisms. Clearly, much about the basic biology of mitochondria remains to be understood. Here we discuss recent work that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease.", "date": "2006-06-30", "date_type": "published", "publication": "Cell", "volume": "125", "number": "7", "publisher": "Elsevier", "pagerange": "1241-1252", "id_number": "CaltechAUTHORS:20170707-131920686", "issn": "0092-8674", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170707-131920686", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.cell.2006.06.010", "primary_object": { "basename": "1-s2.0-S0092867406007689-mmc1.mov", "url": "https://authors.library.caltech.edu/records/1g77s-adw62/files/1-s2.0-S0092867406007689-mmc1.mov" }, "resource_type": "article", "pub_year": "2006", "author_list": "Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/cx1yq-39d46", "eprint_id": 5937, "eprint_status": "archive", "datestamp": "2023-08-22 05:55:02", "lastmod": "2023-10-16 19:59:05", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Griffin-E-E", "name": { "family": "Griffin", "given": "Erik E." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Domain interactions within Fzo1 oligomers are essential for mitochondrial fusion", "ispublished": "pub", "full_text_status": "public", "keywords": "DYNAMIN-RELATED GTPASE; DOMINANT OPTIC ATROPHY; VIRAL MEMBRANE-FUSION; OUTER-MEMBRANE; SACCHAROMYCES-CEREVISIAE; MAMMALIAN HOMOLOGS; COILED COILS; PROTEIN; MGM1P; MECHANISMS", "note": "\u00a9 2006 the American Society for Biochemistry and Molecular Biology. \n\nReceived for publication, February 27, 2006, and in revised form, April 12, 2006 Published, JBC Papers in Press, April 19, 2006, DOI 10.1074/jbc.M601847200 \n\nWe thank Janet Shaw for stimulating discussions on allelic complementation. \n\nThis work was supported in part by National Institutes of Health Grant GM62967 (to D.C.C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked \"advertisement\" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. \n\n[D.C.C. was a] Beckman Young Investigator and Bren Scholar.\n\nPublished - GRIjbc06.pdf
", "abstract": "Mitofusins are conserved GTPases essential for the fusion of mitochondria. These mitochondrial outer membrane proteins contain a GTPase domain and two or three regions with hydrophobic heptad repeats, but little is known about how these domains interact to mediate mitochondrial fusion. To address this issue, we have analyzed the yeast mitofusin Fzo1p and find that mutation of any of the three heptad repeat regions (HRN, HR1, and HR2) leads to a null allele. Specific pairs of null alleles show robust complementation, indicating that functional domains need not exist on the same molecule. Biochemical analysis indicates that this complementation is due to Fzo1p oligomerization mediated by multiple domain interactions. Moreover, we find that two non-overlapping protein fragments, one consisting of HRN/GTPase and the other consisting of HR1/HR2, can form a complex that reconstitutes Fzo1p fusion activity. Each of the null alleles disrupts the interaction of these two fragments, suggesting that we have identified a key interaction involving the GTPase domain and heptad repeats essential for fusion.", "date": "2006-06-16", "date_type": "published", "publication": "Journal of Biological Chemistry", "volume": "281", "number": "24", "publisher": "American Society for Biochemistry and Molecular Biology", "pagerange": "16599-16606", "id_number": "CaltechAUTHORS:GRIjbc06", "issn": "0021-9258", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:GRIjbc06", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM62967" } ] }, "doi": "10.1074/jbc.M601847200", "primary_object": { "basename": "GRIjbc06.pdf", "url": "https://authors.library.caltech.edu/records/cx1yq-39d46/files/GRIjbc06.pdf" }, "resource_type": "article", "pub_year": "2006", "author_list": "Griffin, Erik E. and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/0qeb7-e1280", "eprint_id": 76300, "eprint_status": "archive", "datestamp": "2023-08-19 17:57:25", "lastmod": "2023-10-25 15:37:23", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Soriano-F-X", "name": { "family": "Soriano", "given": "Franscesc X." } }, { "id": "Liesa-M", "name": { "family": "Liesa", "given": "Marc" } }, { "id": "Bach-D", "name": { "family": "Bach", "given": "Daniel" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Pala\u0107in-M", "name": { "family": "Pala\u0107in", "given": "Manuel" } }, { "id": "Zorzano-A", "name": { "family": "Zorzano", "given": "Antonio" } } ] }, "title": "Evidence for a Mitochondrial Regulatory Pathway Defined by Peroxisome Proliferator\u2013Activated Receptor-\u03b3 Coactivator-1\u03b1, Estrogen-Related Receptor-\u03b1, and Mitofusin 2", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2006 American Diabetes Association. \n\nAccepted February 21, 2006. Received April 22, 2005. \n\nThis study was supported by research grants from the Ministerio de Ciencia y Tecnolog\u00eda (SAF 2005-00445), Grant 2005 SGR00947 from the Generalitat de Catalunya, the Fundaci\u00f3 Marat\u00f3 de TV3 (300720), and the Instituto de Salud Carlos III RCMN (C03/08), RGDM (G03/212), and RGTO (G03/028). F.X.S. was the recipient of a predoctoral fellowship from the Instituto Danone and from the University of Barcelona, Barcelona, Spain. M.L. is the recipient of a predoctoral fellowship from the Ministerio de Educaci\u00f3n y Cultura, Spain. \n\nWe thank Tanya Yates for her editorial support, Dr. Diego Haro (University of Barcelona) for his scientific advice, and Drs. Luc Marti, Sara Pich, and Marta Camps for their help in animal studies. \n\nThe costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked \"advertisement\" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.", "abstract": "Here, we report an increase in Mfn2 gene expression under conditions of high energy expenditure mediated by PGC-1\u03b1, and we also demonstrate that PGC-1\u03b1 stimulates Mfn2 gene expression and that this is caused by two elements on the promoter that bind ERR\u03b1. In addition, we show that Mfn2 loss of function attenuates the effects of PGC-1\u03b1 on mitochondrial membrane potential and that cold exposure causes an additional increase in PGC-1\u03b1 in skeletal muscle from mice that are heterozygous knock-out (KO) for Mfn2.", "date": "2006-06", "date_type": "published", "publication": "Diabetes", "volume": "55", "number": "6", "publisher": "American Diabetes Association", "pagerange": "1783-1791", "id_number": "CaltechAUTHORS:20170408-171111529", "issn": "0012-1797", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170408-171111529", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Ministerio de Ciencia Y Tecnologia (MCYT)", "grant_number": "SAF 2005-00445" }, { "agency": "Generalitat de Catalunya", "grant_number": "2005 SGR00947" }, { "agency": "Fundaci\u00f3 Marat\u00f3 de TV3", "grant_number": "300720" }, { "agency": "Instituto de Salud Carlos III", "grant_number": "C03/08" }, { "agency": "Instituto de Salud Carlos III", "grant_number": "G03/212" }, { "agency": "Instituto de Salud Carlos III", "grant_number": "G03/028" }, { "agency": "Instituto Danone" }, { "agency": "University of Barcelona" }, { "agency": "Ministerio de Educaci\u00f3n y Cultura (MEC)" } ] }, "doi": "10.2337/db05-0509", "resource_type": "article", "pub_year": "2006", "author_list": "Soriano, Franscesc X.; Liesa, Marc; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/agm1m-1cg22", "eprint_id": 78870, "eprint_status": "archive", "datestamp": "2023-08-22 05:49:39", "lastmod": "2023-10-26 14:24:55", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Griffin-E-E", "name": { "family": "Griffin", "given": "Erik E." } }, { "id": "Detmer-S-A", "name": { "family": "Detmer", "given": "Scott A." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Molecular mechanism of mitochondrial membrane fusion", "ispublished": "pub", "full_text_status": "restricted", "keywords": "Membrane fusion; Mitochondrial dynamics; Mitochondrial fusion; GTPase; Organelles", "note": "\u00a9 2006 Elsevier B.V. \n\nReceived 16 January 2006, Accepted 14 February 2006, Available online 9 March 2006. \n\nWork in D. Chan's laboratory is funded by the NIH (GM062967), the Muscular Dystrophy Association, and the United Mitochondrial Disease Foundation. D. Chan is a Bren Scholar.", "abstract": "Mitochondrial fusion requires coordinated fusion of the outer and inner membranes. This process leads to exchange of contents, controls the shape of mitochondria, and is important for mitochondrial function. Two types of mitochondrial GTPases are essential for mitochondrial fusion. On the outer membrane, the fuzzy onions/mitofusin proteins form complexes in trans that mediate homotypic physical interactions between adjacent mitochondria and are likely directly involved in outer membrane fusion. Associated with the inner membrane, the OPA1 dynamin-family GTPase maintains membrane structure and is a good candidate for mediating inner membrane fusion. In yeast, Ugo1p binds to both of these GTPases to form a fusion complex, although a related protein has yet to be found in mammals. An understanding of the molecular mechanism of fusion may have implications for Charcot\u2013Marie\u2013Tooth subtype 2A and autosomal dominant optic atrophy, neurodegenerative diseases caused by mutations in Mfn2 and OPA1.", "date": "2006-06", "date_type": "published", "publication": "Biochimica et Biophysica Acta", "volume": "1763", "number": "5-6", "publisher": "Elsevier", "pagerange": "482-489", "id_number": "CaltechAUTHORS:20170707-145340571", "issn": "0167-4889", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170707-145340571", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM062967" }, { "agency": "Muscular Dystrophy Association" }, { "agency": "United Mitochondrial Disease Foundation" }, { "agency": "Bren Scholar" } ] }, "doi": "10.1016/j.bbamcr.2006.02.003", "resource_type": "article", "pub_year": "2006", "author_list": "Griffin, Erik E.; Detmer, Scott A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/6767n-31744", "eprint_id": 78867, "eprint_status": "archive", "datestamp": "2023-08-19 17:37:49", "lastmod": "2023-10-26 14:24:44", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "D." }, "orcid": "0000-0002-0191-2154" }, { "id": "Frank-S", "name": { "family": "Frank", "given": "S." } }, { "id": "Rojo-M", "name": { "family": "Rojo", "given": "M." } } ] }, "title": "Mitochondrial dynamics in cell life and death", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2006 Nature Publishing Group. \n\nPublished online 27 January 2006. \n\nWe assume to speak for all participants of this meeting by thanking the members of the organizing committee (Luca Scorrano, Paolo Bernardi, Tullio Pozzan and Carla Tonin) for the perfect organization of this workshop. The organizing committee gratefully acknowledges the support by the following sponsors: Federation of the European Biochemical Societies (FEBS), International Union of Biochemistry and Molecular Biology (IUBMB), Istituto Veneto di Medicina Molecolare, Comitato Fondazione Telethon ONLUS, Invitrogen Italia SPA, Celbio SPA, Sacco SRL, Elettrofor SAS.", "abstract": "The International FEBS-IUBMB Workshop: 'Mitochondrial Dynamics in Cell Life and Death', 27\u201330 August 2005, was dedicated to the memory of Stanley J Korsmeyer (1950\u20132005). It was held at the Venetian Institute of Molecular Medicine in Padova, a charming city near Venice that hosts a respected university with a long-standing tradition for scientific studies. Galileo Galilei, one of its best-known professors, made some of his most significant discoveries during the 18 years (1592\u20131610) he spent in this city. This meeting was the very first specifically dedicated to mitochondrial dynamics, and reflecting the exciting state of this field, the program was densely packed with innovative talks. Roughly 100 scientists attended 33 talks by invited speakers and 10 talks selected from submitted abstracts. Some 50 posters were displayed throughout the duration of the meeting. Discussions were lively during the conferences, the poster sessions and the breaks on the beautiful terrace of the Institute. The members of the local organizing committee and the friendly personnel of the excellent catering service were rewarded with long applauses from all participants. We apologize for the other numerous excellent contributions that could not be included into this report owing to space limitations.", "date": "2006-04", "date_type": "published", "publication": "Cell Death and Differentiation", "volume": "13", "number": "4", "publisher": "Nature Publishing", "pagerange": "680-684", "id_number": "CaltechAUTHORS:20170707-141353341", "issn": "1350-9047", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170707-141353341", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Federation of the European Biochemical Societies (FEBS)" }, { "agency": "International Union of Biochemistry and Molecular Biology (IUBMB)" }, { "agency": "Istituto Veneto di Medicina Molecolare" }, { "agency": "Comitato Fondazione Telethon ONLUS" }, { "agency": "Invitrogen Italia SPA" }, { "agency": "Celbio SPA" }, { "agency": "Sacco SRL" }, { "agency": "Elettrofor SAS" } ] }, "doi": "10.1038/sj.cdd.4401857", "resource_type": "article", "pub_year": "2006", "author_list": "Chan, D.; Frank, S.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/5zhwd-hnf51", "eprint_id": 5765, "eprint_status": "archive", "datestamp": "2023-08-22 04:18:41", "lastmod": "2023-10-16 19:24:20", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Emerging functions of mammalian mitochondrial fusion and fission", "ispublished": "pub", "full_text_status": "public", "keywords": "DOMINANT OPTIC ATROPHY; DYNAMIN-RELATED PROTEIN; MARIE-TOOTH-DISEASE; WD REPEAT PROTEIN; OPA1 MUTATIONS; APOPTOSIS; GTPASE; MORPHOLOGY; DIVISION; CELLS", "note": "\u00a9 The Author 2005. Published by Oxford University Press. \n\nReceived June 8, 2005; accepted July 14, 2005. \n\nConflict of Interest statement. None declared.", "abstract": "Mitochondria provide a myriad of services to the cell, including energy production, calcium buffering and regulation of apoptosis. How these diverse functions are coordinated among the hundreds of mitochondria in a given cell is largely unknown, but is probably dependent on the dynamic nature of mitochondria. In this review, we explore the latest developments in mitochondrial dynamics in mammals. These studies indicate that mitofusins and OPA1 are essential for mitochondrial fusion, whereas Fis1 and Drp1 are essential for mitochondrial fission. The overall morphology of the mitochondrial population depends on the relative activities of these two sets of proteins. In addition to the regulation of mitochondrial shape, these molecules also play important roles in cell and tissue physiology. Perturbation of mitochondrial fusion results in defects in mitochondrial membrane potential and respiration, poor cell growth and increased susceptibility to cell death. These cellular observations may explain why mitochondrial fusion is essential for embryonic development. Two inherited neuropathies, Charcot\u2013Marie\u2013Tooth type 2A and autosomal dominant optic atrophy, are caused by mutations in mitofusin 2 and OPA1, suggesting that proper regulation of mitochondrial dynamics is particularly vital to neurons. Mitochondrial fission accompanies several types of apoptotic cell death and appears important for progression of the apoptotic pathway. These studies provide insight into how mitochondria communicate with one another to coordinate mitochondrial function and morphology.", "date": "2005-10-15", "date_type": "published", "publication": "Human Molecular Genetics", "volume": "14", "number": "2", "publisher": "Oxford University Press", "pagerange": "R283-R289", "id_number": "CaltechAUTHORS:CHEhmg05", "issn": "0964-6906", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHEhmg05", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "primary_object": { "basename": "CHEhmg05.pdf", "url": "https://authors.library.caltech.edu/records/5zhwd-hnf51/files/CHEhmg05.pdf" }, "resource_type": "article", "pub_year": "2005", "author_list": "Chen, Hsiuchen and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/qyr51-6zg13", "eprint_id": 5315, "eprint_status": "archive", "datestamp": "2023-08-22 03:56:47", "lastmod": "2023-10-16 19:09:22", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Griffin-E-E", "name": { "family": "Griffin", "given": "Erik E." } }, { "id": "Graumann-J", "name": { "family": "Graumann", "given": "Johannes" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "The WD40 protein Caf4p is a component of the mitochondrial fission machinery and recruits Dnm1p to mitochondria", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 The Rockefeller University Press, 2005 \n\nSubmitted: 25 March 2005; Accepted: 9 June 2005; Published online July 11, 2005. doi:10.1083/jcb.200503148 \n\nWe thank T.R. Suntoke, S.A. Detmer, and H. Chen for helpful comments on the manuscript; and L. Lytle for technical assistance. J. Copeland constructed some of the two-hybrid plasmids. We thank Dr. Ray Deshaies for stimulating discussions on mass spectrometry. \n\nE.E. Griffin was supported by a National Institutes of Health training grant (NIH GM07616) and a Ferguson fellowship. MudPIT analysis was performed in the mass spectrometry facility of the laboratory of R.J. Deshaies (Investigator, Howard Hughes Medical Institute, Caltech). This facility is supported by the Beckman Institute at Caltech and by a grant from the Department of Energy to R.J. Deshaies and B.J. Wold. J. Graumann is supported by R.J. Deshaies through Howard Hughes Medical Institute funds. D.C. Chan is a Bren Scholar and Beckman Young Investigator. This research was supported by the National Institutes of Health (GM62967). \n\nTable S1 lists proteins identified in MudPIT experiments with M9TH-Fis1p. Table S2 shows yeast strains. Table S3 lists primer sequences. Videos 1 and 2 show mitochondrial fission in mdv1{Delta} yeast. Mitochondria were monitored by the mitochondrial outer membrane marker OM45-GFP. Arrows highlight a subset of fission events. Online supplemental material available at http://www.jcb.org/cgi/content/full/jcb.200503148/DC1.\n\nPublished - GRIjcb05.pdf
", "abstract": "The mitochondrial division machinery regulates mitochondrial dynamics and consists of Fis1p, Mdv1p, and Dnm1p. Mitochondrial division relies on the recruitment of the dynamin-related protein Dnm1p to mitochondria. Dnm1p recruitment depends on the mitochondrial outer membrane protein Fis1p. Mdv1p interacts with Fis1p and Dnm1p, but is thought to act at a late step during fission because Mdv1p is dispensable for Dnm1p localization. We identify the WD40 repeat protein Caf4p as a Fis1p-associated protein that localizes to mitochondria in a Fis1p-dependent manner. Caf4p interacts with each component of the fission apparatus: with Fis1p and Mdv1p through its NH2-terminal half and with Dnm1p through its COOH-terminal WD40 domain. We demonstrate that mdv1{Delta} yeast contain residual mitochondrial fission due to the redundant activity of Caf4p. Moreover, recruitment of Dnm1p to mitochondria is disrupted in mdv1{Delta} caf4{Delta} yeast, demonstrating that Mdv1p and Caf4p are molecular adaptors that recruit Dnm1p to mitochondrial fission sites. Our studies support a revised model for assembly of the mitochondrial fission apparatus.", "date": "2005-07-18", "date_type": "published", "publication": "Journal of Cell Biology", "volume": "170", "number": "2", "publisher": "Rockefeller University Press", "pagerange": "237-248", "id_number": "CaltechAUTHORS:GRIjcb05", "issn": "0021-9525", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:GRIjcb05", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1083/jcb.200503148", "pmcid": "PMC2171414", "primary_object": { "basename": "GRIjcb05.pdf", "url": "https://authors.library.caltech.edu/records/qyr51-6zg13/files/GRIjcb05.pdf" }, "resource_type": "article", "pub_year": "2005", "author_list": "Griffin, Erik E.; Graumann, Johannes; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/tzphd-1sv40", "eprint_id": 4084, "eprint_status": "archive", "datestamp": "2023-08-22 03:56:04", "lastmod": "2023-10-16 17:36:18", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chomyn-A", "name": { "family": "Chomyn", "given": "Anne" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Disruption of fusion results in mitochondrial heterogeneity and dysfunction", "ispublished": "pub", "full_text_status": "public", "keywords": "DOMINANT OPTIC ATROPHY; DYNAMIN-RELATED GTPASE; MORPHOLOGY; OPA1; PROTEASE; CELLS; COMPLEMENTATION; MITOFUSIN-1; EXPRESSION; APOPTOSIS", "note": "\u00a9 2005 The American Society for Biochemistry and Molecular Biology, Inc. \n\nReceived for publication, March 21, 2005; published, JBC Papers in Press, May 17, 2005. \n\nWe are grateful to Drs. G. Hernandez-Hoyos, J. Ila-Alberola, J. Rossi, L. Griparic, and A. van der Bliek for generous gifts of plasmids and antibody. We thank Dr. J. Pomerantz for useful advice on RNAi.\n\nPublished - CHEjbc05.pdf
", "abstract": "Mitochondria undergo continual cycles of fusion and fission, and the balance of these opposing processes regulates mitochondrial morphology. Paradoxically, cells invest many resources to maintain tubular mitochondrial morphology, when reducing both fusion and fission simultaneously achieves the same end. This observation suggests a requirement for mitochondrial fusion, beyond maintenance of organelle morphology. Here, we show that cells with targeted null mutations in Mfn1 or Mfn2 retained low levels of mitochondrial fusion and escaped major cellular dysfunction. Analysis of these mutant cells showed that both homotypic and heterotypic interactions of Mfns are capable of fusion. In contrast, cells lacking both Mfn1 and Mfn2 completely lacked mitochondrial fusion and showed severe cellular defects, including poor cell growth, widespread heterogeneity of mitochondrial membrane potential, and decreased cellular respiration. Disruption of OPA1 by RNAi also blocked all mitochondrial fusion and resulted in similar cellular defects. These defects in Mfn-null or OPA1-RNAi mammalian cells were corrected upon restoration of mitochondrial fusion, unlike the irreversible defects found in fzo yeast. In contrast, fragmentation of mitochondria, without severe loss of fusion, did not result in such cellular defects. Our results showed that key cellular functions decline as mitochondrial fusion is progressively abrogated.", "date": "2005-07-15", "date_type": "published", "publication": "Journal of Biological Chemistry", "volume": "280", "number": "28", "publisher": "American Society for Biochemistry and Molecular Biology", "pagerange": "26185-26192", "id_number": "CaltechAUTHORS:CHEjbc05", "issn": "0021-9258", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHEjbc05", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1074/jbc.M503062200", "primary_object": { "basename": "CHEjbc05.pdf", "url": "https://authors.library.caltech.edu/records/tzphd-1sv40/files/CHEjbc05.pdf" }, "resource_type": "article", "pub_year": "2005", "author_list": "Chen, Hsiuchen; Chomyn, Anne; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/43vag-6mt40", "eprint_id": 6840, "eprint_status": "archive", "datestamp": "2023-08-22 03:40:25", "lastmod": "2023-10-16 20:34:00", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Suntoke-Tara-R", "name": { "family": "Suntoke", "given": "Tara R." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "The Fusion Activity of HIV-1 gp41 Depends on Interhelical Interactions", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2005 the American Society for Biochemistry and Molecular Biology. \n\nReceived for publication, February 25, 2005. Originally published In Press as doi:10.1074/jbc.M502196200 on March 16, 2005. \n\nWe thank Drs. R. Olsen and A. Herr for assistance with the sedimentation equilibrium experiments, Dr. J. Kaiser for help with Fig. 1C, Drs. D. Eckert and M. Kay for critical review of the manuscript, and E. Griffin and members of the Chan lab for helpful discussions. \n\nThis work was supported in part by National Institutes of Health Grant PO1 GM56552. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked \"advertisement\" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. \n\nSupported by the Massachusetts Institute of Technology and Merck Pharmaceuticals.\n\nPublished - SUNjbc05.pdf
", "abstract": "Infection by human immunodeficiency virus type I requires the fusogenic activity of gp41, the transmembrane subunit of the viral envelope protein. Crystallographic studies have revealed that fusion-active gp41 is a \"trimer-of-hairpins\" in which three central N-terminal helices form a trimeric coiled coil surrounded by three antiparallel C-terminal helices. This structure is stabilized primarily by hydrophobic, interhelical interactions, and several critical contacts are made between residues that form a deep cavity in the N-terminal trimer and the C-helix residues that pack into this cavity. In addition, the trimer-of-hairpins structure has an extensive network of hydrogen bonds within a conserved glutamine-rich layer of poorly understood function. Formation of the trimer-of-hairpins structure is thought to directly force the viral and target membranes together, resulting in membrane fusion and viral entry. We test this hypothesis by constructing four series of gp41 mutants with disrupted interactions between the N- and C-helices. Notably, in the three series containing mutations within the cavity, gp41 activity correlates well with the stability of the N-C interhelical interaction. In contrast, a fourth series of mutants involving the glutamine layer residue Gln-653 show fusion defects even though the stability of the hairpin is close to wild-type. These results provide evidence that gp41 hairpin stability is critical for mediating fusion and suggest a novel role for the glutamine layer in gp41 function.", "date": "2005-05-20", "date_type": "published", "publication": "Journal of Biological Chemistry", "volume": "280", "number": "20", "publisher": "American Society for Biochemistry and Molecular Biology", "pagerange": "19852-19857", "id_number": "CaltechAUTHORS:SUNjbc05", "issn": "0021-9258", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:SUNjbc05", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "PO1 GM56552" }, { "agency": "Massachusetts Institute of Technology (MIT)" }, { "agency": "Merck" } ] }, "doi": "10.1074/jbc.M502196200", "primary_object": { "basename": "SUNjbc05.pdf", "url": "https://authors.library.caltech.edu/records/43vag-6mt40/files/SUNjbc05.pdf" }, "resource_type": "article", "pub_year": "2005", "author_list": "Suntoke, Tara R. and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/3tvj7-qxz63", "eprint_id": 51999, "eprint_status": "archive", "datestamp": "2023-08-19 14:05:00", "lastmod": "2023-10-18 19:14:41", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Koshiba-T", "name": { "family": "Koshiba", "given": "Takumi" } }, { "id": "Detmer-S-A", "name": { "family": "Detmer", "given": "Scott A." } }, { "id": "Kaiser-J-T", "name": { "family": "Kaiser", "given": "Jens T." }, "orcid": "0000-0002-5948-5212" }, { "id": "Chen-H", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "McCaffery-J-M", "name": { "family": "McCaffery", "given": "J. Michael" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Structural Basis of Mitochondrial Tethering by Mitofusin Complexes", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2004 American Association for the Advancement of Science.\n30 April 2004; accepted 30 June 2004. \n\nWe are grateful to D. Rees, J. Nunnari, and R. Deshaies\nfor helpful discussions. We thank the staff of the Advanced\nLight Source at Berkeley Lab. We thank P. Huang\nfor advice on structural analysis. T.K. was supported by\na Gosney Foundation postdoctoral fellowship; J.T.K. is\nan HHMI Research Associate. This work was supported\nby the National Institute of Health (R01 GM62967).\nD.C.C. is a Bren Scholar, Rita Allen Scholar, and Beckman\nYoung Investigator. Atomic coordinates and structure\nfactors have been deposited in the Protein Data Bank,\naccession code 1T3J.", "abstract": "Vesicle fusion involves vesicle tethering, docking, and membrane merger. We show that mitofusin, an integral mitochondrial membrane protein, is required on adjacent mitochondria to mediate fusion, which indicates that mitofusin complexes act in trans (that is, between adjacent mitochondria). A heptad repeat region (HR2) mediates mitofusin oligomerization by assembling a dimeric, antiparallel coiled coil. The transmembrane segments are located at opposite ends of the 95 angstrom coiled coil and provide a mechanism for organelle tethering. Consistent with this proposal, truncated mitofusin, in an HR2-dependent manner, causes mitochondria to become apposed with a uniform gap. Our results suggest that HR2 functions as a mitochondrial tether before fusion.", "date": "2004-08-06", "date_type": "published", "publication": "Science", "volume": "305", "number": "5685", "publisher": "American Association for the Advancement of Science", "pagerange": "858-862", "id_number": "CaltechAUTHORS:20141120-103756939", "issn": "0036-8075", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141120-103756939", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Gosney Foundation" }, { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "NIH", "grant_number": "R01 GM62967" } ] }, "doi": "10.1126/science.1099793", "resource_type": "article", "pub_year": "2004", "author_list": "Koshiba, Takumi; Detmer, Scott A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/12w28-frh77", "eprint_id": 78884, "eprint_status": "archive", "datestamp": "2023-08-19 13:14:50", "lastmod": "2023-10-26 14:25:44", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitochondrial Dynamics in Mammals", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2004 Elsevier Inc. \n\nAvailable online 4 March 2004.", "abstract": "This chapter discusses the role of mitochondria dynamics in mammalian mitochondrial morphology, mitochondrial function, disease, embryogenesis, and apoptosis. It defines mitochondria as static, kidney bean-shaped organelles that have the mundane chore of providing energy for the cell. The mitochondrial population is, in fact, dynamic, and the hundreds of mitochondria in a cell can have a range of morphologies, including small spheres, long tubules, and interconnected tubules. This morphological plasticity is based on the ability of mitochondria to undergo both organellar fusion and fission. The chapter reviews the current molecular understanding of mitochondrial fusion and fission. Several observations indicate that mitochondrial dynamics plays a significant role in vertebrate cells. The time-lapse observations of mammalian cells reveal frequent and constant cycles of mitochondrial fusion and fission. The identification of molecules involved in the fusion and fission pathways has allowed an assessment of their relative roles in controlling mitochondrial morphology. The chapter also discusses the importance of mitochondrial dynamics in human physiology.", "date": "2004-03-04", "date_type": "published", "publication": "Current Topics in Developmental Biology", "volume": "59", "publisher": "Elsevier", "pagerange": "119-144", "id_number": "CaltechAUTHORS:20170710-085130148", "issn": "0070-2153", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170710-085130148", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/S0070-2153(04)59005-1", "resource_type": "article", "pub_year": "2004", "author_list": "Chen, Hsiuchen and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/5qnqf-d2h39", "eprint_id": 6786, "eprint_status": "archive", "datestamp": "2023-08-22 01:33:57", "lastmod": "2023-10-16 20:32:05", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Karbowski-M", "name": { "family": "Karbowski", "given": "Mariusz" } }, { "id": "Arnoult-D", "name": { "family": "Arnoult", "given": "Damien" } }, { "id": "Chen-Hsuichen", "name": { "family": "Chen", "given": "Hsuichen" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Smith-C-L", "name": { "family": "Smith", "given": "Carolyn L." } }, { "id": "Youle-R-J", "name": { "family": "Youle", "given": "Richard J." } } ] }, "title": "Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis", "ispublished": "pub", "full_text_status": "public", "keywords": "dynamin; fission; Opal; PAGFP; photoactivation", "note": "\u00a9 2004 The Rockefeller University Press. \n\nSubmitted: 11 September 2003. Accepted: 6 January 2004. Published online 9 February 2004. doi:10.1083/jcb.200309082 \n\nThe authors thank G.H. Patterson and J. Lippincott-Schwartz for PAGFP vectors, C. Blackstone for critical reading of the manuscript, C.A. Winters for neurons, and R. Raju and M. Dalakas for myocytes. \n\nOnline supplemental material\nFig. S1 shows a correlation between the changes in the mitochondrial morphology and the release of endogenous cytochrome c from mitochondria and a conformational change in the endogenous Bax protein. Online supplemental material is available at http://www.jcb.org/cgi/content/full/jcb.200309082/DC1.\n\nPublished - KARjcb04.pdf
Supplemental Material - KARjcb04fig1.gif
Supplemental Material - KARjcb04fig2ab.gif
Supplemental Material - KARjcb04fig2cd.jpg
Supplemental Material - KARjcb04fig3ac.jpg
Supplemental Material - KARjcb04fig3df.jpg
Supplemental Material - KARjcb04fig4.gif
Supplemental Material - KARjcb04fig5.gif
Supplemental Material - KARjcb04figS1.jpg
Supplemental Material - KARjcb04suppmatmeth.pdf
", "abstract": "A dynamic balance of organelle fusion and fission regulates mitochondrial morphology. During apoptosis this balance is altered, leading to an extensive fragmentation of the mitochondria. Here, we describe a novel assay of mitochondrial dynamics based on confocal imaging of cells expressing a mitochondrial matrix\u2013targeted photoactivable green fluorescent protein that enables detection and quantification of organelle fusion in living cells. Using this assay, we visualize and quantitate mitochondrial fusion rates in healthy and apoptotic cells. During apoptosis, mitochondrial fusion is blocked independently of caspase activation. The block in mitochondrial fusion occurs within the same time range as Bax coalescence on the mitochondria and outer mitochondrial membrane permeabilization, and it may be a consequence of Bax/Bak activation during apoptosis.", "date": "2004-02-16", "date_type": "published", "publication": "Journal of Cell Biology", "volume": "164", "number": "4", "publisher": "Rockefeller University Press", "pagerange": "493-499", "id_number": "CaltechAUTHORS:KARjcb04", "issn": "0021-9525", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:KARjcb04", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1083/jcb.200309082", "pmcid": "PMC2172000", "primary_object": { "basename": "KARjcb04fig2cd.jpg", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/KARjcb04fig2cd.jpg" }, "related_objects": [ { "basename": "KARjcb04fig5.gif", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/KARjcb04fig5.gif" }, { "basename": "KARjcb04suppmatmeth.pdf", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/KARjcb04suppmatmeth.pdf" }, { "basename": "KARjcb04.pdf", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/KARjcb04.pdf" }, { "basename": "KARjcb04fig2ab.gif", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/KARjcb04fig2ab.gif" }, { "basename": "KARjcb04fig3ac.jpg", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/KARjcb04fig3ac.jpg" }, { "basename": "KARjcb04fig3df.jpg", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/KARjcb04fig3df.jpg" }, { "basename": "KARjcb04fig4.gif", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/KARjcb04fig4.gif" }, { "basename": "KARjcb04figS1.jpg", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/KARjcb04figS1.jpg" }, { "basename": "medium.png", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/medium.png" }, { "basename": "small.png", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/small.png" }, { "basename": "KARjcb04fig1.gif", "url": "https://authors.library.caltech.edu/records/5qnqf-d2h39/files/KARjcb04fig1.gif" } ], "resource_type": "article", "pub_year": "2004", "author_list": "Karbowski, Mariusz; Arnoult, Damien; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/dbmgk-77n76", "eprint_id": 5173, "eprint_status": "archive", "datestamp": "2023-08-22 00:15:03", "lastmod": "2023-10-16 19:04:24", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Koshiba-Takumi", "name": { "family": "Koshiba", "given": "Takumi" } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "The Prefusogenic Intermediate of HIV-1 gp41 Contains Exposed C-peptide Regions", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2003 The American Society for Biochemistry and Molecular Biology, Inc. \n\nReceived for publication, October 31, 2002. Published, JBC Papers in Press, December 13, 2002, DOI 10.1074/jbc.M211154200. \n\nWe gratefully acknowledge Drs. Michael J. Root and Peter S. Kim for providing the p5-Helix and p6-Helix vectors. We also thank Dr. Peter S. Kim for critical reading of the manuscript and members of the Chan lab for helpful comments on the manuscript. \n\nThis work was supported by National Institutes of Health Grant 7 PO1 GM56552-05 and by a Burroughs Wellcome Fund Career Development Award in Biomedical Sciences.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked \"advertisement\" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. \n\n[T.K. was a] Postdoctoral fellow of the Japan Society for the Promotion of Science. \n\n[D.C.C. was a] Bren Scholar [and a] Rita Allen Scholar.\n\nPublished - KOSjbc03.pdf
", "abstract": "The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein is composed of a complex between the surface subunit gp120, which binds to cellular receptors, and the transmembrane subunit gp41. Upon activation of the envelope glycoprotein by cellular receptors, gp41 undergoes conformational changes that mediate fusion of the viral and cellular membranes. Prior to formation of a fusogenic \"trimer-of-hairpins\" structure, gp41 transiently adopts a prefusogenic conformation whose structural features are poorly understood. An important approach toward understanding structural conformations of gp41 during HIV-1 entry has been to analyze the structural targets of gp41 inhibitors. We have constructed epitope-tagged versions of 5-Helix, a designed protein that binds to the C-peptide region of gp41 and inhibits HIV-1 membrane fusion. Using these 5-Helix variants, we examined which conformation of gp41 is the target of 5-Helix. We find that although 5-Helix binds poorly to native gp41, it binds strongly to gp41 activated by interaction of the envelope protein with either soluble CD4 or membrane-bound cellular receptors. This preferential interaction with activated gp41 results in the accumulation of 5-Helix on the surface of activated cells. These results strongly suggest that the gp41 prefusogenic intermediate is the target of 5-Helix and that this intermediate has a remarkably \"open\" structure, with exposed C-peptide regions. These results provide important structural information about this intermediate that should facilitate the development of HIV-1 entry inhibitors and may lead to new vaccine strategies.", "date": "2003-02-28", "date_type": "published", "publication": "Journal of Biological Chemistry", "volume": "278", "number": "9", "publisher": "American Society for Biochemistry and Molecular Biology", "pagerange": "7573-7579", "id_number": "CaltechAUTHORS:KOSjbc03", "issn": "0021-9258", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:KOSjbc03", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "7 PO1 GM56552-05" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "Japan Society for the Promotion of Science (JSPS)" }, { "agency": "Bren Foundation" }, { "agency": "Rita Allen Foundation" } ] }, "doi": "10.1074/jbc.M211154200", "primary_object": { "basename": "KOSjbc03.pdf", "url": "https://authors.library.caltech.edu/records/dbmgk-77n76/files/KOSjbc03.pdf" }, "resource_type": "article", "pub_year": "2003", "author_list": "Koshiba, Takumi and Chan, David C." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/xy3jg-4h049", "eprint_id": 27425, "eprint_status": "archive", "datestamp": "2023-08-19 10:52:37", "lastmod": "2023-10-24 17:08:48", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Hsiuchen", "name": { "family": "Chen", "given": "Hsiuchen" } }, { "id": "Detmer-S-A", "name": { "family": "Detmer", "given": "Scott A." } }, { "id": "Ewald-A-J", "name": { "family": "Ewald", "given": "Andrew J." } }, { "id": "Griffin-E-E", "name": { "family": "Griffin", "given": "Erik E." } }, { "id": "Fraser-S-E", "name": { "family": "Fraser", "given": "Scott E." }, "orcid": "0000-0002-5377-0223" }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" } ] }, "title": "Mitofusins Mfn1 and Mfn2 coordinately regulate\n mitochondrial fusion and are essential for embryonic development", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2003 Rockefeller University Press. \n\nThe online version of this article contains supplemental material. Submitted: 12 November 2002. Accepted: 12 December 2002. Revision received 12 December 2002. \n\nWe thank Dr. Philip Leder for his support in the early stages of this work. We are grateful to M. Michelman for embryonic stem cell culture assistance and A. Harrington for blastocyst injections. We thank Drs. M. Rojo and A. Lombes for stimulating discussions about the PEG fusion assay. H. Chen is supported by an Alcott Postdoctoral fellowship. S.A. Detmer\nand E.E. Griffin are supported by a National Institutes of Health training grant NIHGM07616 and E.E. Griffin is funded by a Ferguson fellowship. A.J. Ewald is a participant in the Initiative in Computational Molecular Biology\nfunded by the Burroughs Wellcome Fund Interfaces program. D.C. Chan is a Bren scholar, Rita Allen scholar, Beckman Young investigator, and recipient of a Burroughs Wellcome Fund Career Development award in Biomedical Sciences. This research was supported by the National Institutes of Health (grant 1 RO1 GM62967-01).\n\nPublished - CHEjcb03.pdf
Supplemental Material - J_Cell_Biol_2003_Jan_160_2__189-200,_Figures.ppt
", "abstract": "Mitochondrial morphology is determined by a dynamic equilibrium between organelle fusion and fission, but the significance of these processes in vertebrates is unknown. The mitofusins, Mfn1 and Mfn2, have been shown to affect mitochondrial morphology when overexpressed. We find that mice deficient in either Mfn1 or Mfn2 die in midgestation. However, whereas Mfn2 mutant embryos have a specific and severe disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells are normal. Embryonic fibroblasts lacking Mfn1 or Mfn2 display distinct types of fragmented mitochondria, a phenotype we determine to be due to a severe reduction in mitochondrial fusion. Moreover, we find that Mfn1 and Mfn2 form homotypic and heterotypic complexes and show, by rescue of mutant cells, that the homotypic complexes are functional for fusion. We conclude that Mfn1 and Mfn2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion. Strikingly, a subset of mitochondria in mutant cells lose membrane potential. Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population.", "date": "2003-01-20", "date_type": "published", "publication": "Journal of Cell Biology", "volume": "160", "number": "2", "publisher": "Rockefeller University Press", "pagerange": "189-200", "id_number": "CaltechAUTHORS:20111025-153633703", "issn": "0021-9525", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20111025-153633703", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Alcott Postdoctoral fellowship" }, { "agency": "NIH", "grant_number": "NIHGM07616" }, { "agency": "Ferguson Fellowship" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "NIH", "grant_number": "1 RO1 GM62967-01" } ] }, "doi": "10.1083/jcb.200211046", "pmcid": "PMC2172648", "primary_object": { "basename": "CHEjcb03.pdf", "url": "https://authors.library.caltech.edu/records/xy3jg-4h049/files/CHEjcb03.pdf" }, "related_objects": [ { "basename": "J_Cell_Biol_2003_Jan_160_2__189-200,_Figures.ppt", "url": "https://authors.library.caltech.edu/records/xy3jg-4h049/files/J_Cell_Biol_2003_Jan_160_2__189-200,_Figures.ppt" } ], "resource_type": "article", "pub_year": "2003", "author_list": "Chen, Hsiuchen; Detmer, Scott A.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/j8h5t-eg422", "eprint_id": 78866, "eprint_status": "archive", "datestamp": "2023-08-19 03:39:44", "lastmod": "2023-10-26 14:24:42", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Chutkowski-C-T", "name": { "family": "Chutkowski", "given": "C. T." } }, { "id": "Kim-Peter-S", "name": { "family": "Kim", "given": "Peter-S" } } ] }, "title": "Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1998 National Academy of Sciences. \n\nContributed by Peter S. Kim, October 23, 1998. \n\nWe are grateful to Michael Burgess, James Pang, and Roberta Moro for peptide synthesis and mass spectrometry support. We also thank Dr. Benjamin Chen for providing reagents and helpful advice on viral infection assays, Drs. Nathaniel Landau and Monty Krieger for providing cell lines, Dr. Michael Root for helpful advice regarding data analysis, and the Kim lab for stimulating discussions and comments on the manuscript. D.C.C. was supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research and is a recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences. This research was funded by the National Institutes of Health (PO1 GM56552). \n\nThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked \"advertisement\" in accordance with 18 U.S.C. \u00a71734 solely to indicate this fact.\n\nPublished - PNAS-1998-Chan-15613-7.pdf
", "abstract": "Synthetic C peptides, corresponding to the C helix of the HIV type 1 (HIV-1) gp41 envelope protein, are potent inhibitors of HIV-1 membrane fusion. One such peptide is in clinical trials. The crystal structure of the gp41 core, in its proposed fusion-active conformation, is a trimer of helical hairpins in which three C helices pack against a central coiled coil. Each C helix shows especially prominent contacts with one of three symmetry-related, hydrophobic cavities on the surface of the coiled coil. We show that the inhibitory activity of the C peptide C34 depends on its ability to bind to this coiled-coil cavity. Moreover, examining a series of C34 peptide variants with modified cavity-binding residues, we find a linear relationship between the logarithm of the inhibitory potency and the stability of the corresponding helical-hairpin complexes. Our results provide strong evidence that this coiled-coil cavity is a good drug target and clarify the mechanism of C peptide inhibition. They also suggest simple, quantitative assays for the identification and evaluation of analogous inhibitors of HIV-1 entry.", "date": "1998-12-22", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "95", "number": "26", "publisher": "National Academy of Sciences", "pagerange": "15613-15617", "id_number": "CaltechAUTHORS:20170707-135940010", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170707-135940010", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Jane Coffin Childs Memorial Fund for Medical Research" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "NIH", "grant_number": "PO1 GM56552" } ] }, "doi": "10.1073/pnas.95.26.15613", "pmcid": "PMC28092", "primary_object": { "basename": "PNAS-1998-Chan-15613-7.pdf", "url": "https://authors.library.caltech.edu/records/j8h5t-eg422/files/PNAS-1998-Chan-15613-7.pdf" }, "resource_type": "article", "pub_year": "1998", "author_list": "Chan, David C.; Chutkowski, C. T.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/05sjy-fmk37", "eprint_id": 78871, "eprint_status": "archive", "datestamp": "2023-08-19 03:13:02", "lastmod": "2023-10-26 14:24:59", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Malashkevich-V-N", "name": { "family": "Malashkevich", "given": "Vladimir N." } }, { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Chutkowski-C-T", "name": { "family": "Chutkowski", "given": "Christine T." } }, { "id": "Kim-Peter-S", "name": { "family": "Kim", "given": "Peter S." } } ] }, "title": "Crystal structure of the simian immunodeficiency virus (SIV) gp41 core: Conserved helical interactions underlie the broad inhibitory activity of gp41 peptides", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 1998 National Academy of Sciences. \n\nContributed by Peter S. Kim, June 9, 1998. \n\nWe thank Michael Burgess, James Pang, and Roberta Moro for peptide synthesis support, and Dr. Benjamin Chen for reagents and helpful advice on viral infection assays. D.C.C. is supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. This research was funded by the National Institutes of Health (PO1 GM56552) and utilized the W. M. Keck Foundation X-Ray Crystallography Facility at the Whitehead Institute. \n\nData deposition: The atomic coordinates have been deposited in the Protein Data Bank, Biology Department, Brookhaven National Laboratory, Upton, NY 11973 (PDB ID code 2 siv) and are available immediately at the website http://www.wi.mit.edu/kim/home.html. \n\nThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked \"advertisement\" in accordance with 18 U.S.C. \u00a71734 solely to indicate this fact.\n\nPublished - PNAS-1998-Malashkevich-9134-9.pdf
", "abstract": "The gp41 subunit of the envelope protein complex from human and simian immunodeficiency viruses (HIV and SIV) mediates membrane fusion during viral entry. The crystal structure of the HIV-1 gp41 ectodomain core in its proposed fusion-active state is a six-helix bundle. Here we have reconstituted the core of the SIV gp41 ectodomain with two synthetic peptides called SIV N36 and SIV C34, which form a highly helical trimer of heterodimers. The 2.2 \u00c5 resolution crystal structure of this SIV N36/C34 complex is very similar to the analogous structure in HIV-1 gp41. In both structures, three N36 helices form a central trimeric coiled coil. Three C34 helices pack in an antiparallel orientation into highly conserved, hydrophobic grooves along the surface of this coiled coil. The conserved nature of the N36-C34 interface suggests that the HIV-1 and SIV peptides are functionally interchangeable. Indeed, a heterotypic complex between HIV-1 N36 and SIV C34 peptides is highly helical and stable. Moreover, as with HIV-1 C34, the SIV C34 peptide is a potent inhibitor of HIV-1 infection. These results identify conserved packing interactions between the N and C helices of gp41 and have implications for the development of C peptide analogs with broad inhibitory activity.", "date": "1998-08-04", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "95", "number": "16", "publisher": "National Academy of Sciences", "pagerange": "9134-9139", "id_number": "CaltechAUTHORS:20170707-145412080", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170707-145412080", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Jane Coffin Childs Memorial Fund for Medical Research" }, { "agency": "NIH", "grant_number": "PO1 GM56552" } ] }, "pmcid": "PMC21304", "primary_object": { "basename": "PNAS-1998-Malashkevich-9134-9.pdf", "url": "https://authors.library.caltech.edu/records/05sjy-fmk37/files/PNAS-1998-Malashkevich-9134-9.pdf" }, "resource_type": "article", "pub_year": "1998", "author_list": "Malashkevich, Vladimir N.; Chan, David C.; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/qgk7m-g9g38", "eprint_id": 78856, "eprint_status": "archive", "datestamp": "2023-08-19 02:55:13", "lastmod": "2023-10-26 14:24:07", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Kim-Peter-S", "name": { "family": "Kim", "given": "Peter S." } } ] }, "title": "HIV Entry and Its Inhibition", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 1998 Cell Press.", "abstract": "The human immunodeficiency virus type 1 (HIV-1) is an enveloped virus, and its envelope protein complex controls the key process of viral entry. This envelope protein determines viral tropism and facilitates the membrane fusion process that allows invasion of the viral genome. The envelope protein can also promote the fusion of infected cells with uninfected neighboring cells, a phenomenon called syncytium formation that is readily observed in cultured cells and may be responsible for some of the cytopathic effects of advanced HIV infection. Here we review recent insights in HIV envelope protein structure and function and present our current understanding of the entry process. We also review how these findings lead to new approaches for inhibiting HIV entry and may provide insights into the design of better HIV vaccines.", "date": "1998-05-29", "date_type": "published", "publication": "Cell", "volume": "93", "number": "5", "publisher": "Elsevier", "pagerange": "681-684", "id_number": "CaltechAUTHORS:20170707-123731974", "issn": "0092-8674", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170707-123731974", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/S0092-8674(00)81430-0", "resource_type": "article", "pub_year": "1998", "author_list": "Chan, David C. and Kim, Peter S." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/twwq6-bsr22", "eprint_id": 78860, "eprint_status": "archive", "datestamp": "2023-08-19 01:16:49", "lastmod": "2023-10-26 14:24:17", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Fass-D", "name": { "family": "Fass", "given": "Deborah" } }, { "id": "Berger-J-M", "name": { "family": "Berger", "given": "James M." } }, { "id": "Kim-Peter-S", "name": { "family": "Kim", "given": "Peter S." } } ] }, "title": "Core Structure of gp41 from the HIV Envelope Glycoprotein", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 1997 Cell Press. \n\nReceived 3 April 1997, Revised 7 April 1997. \n\nWe thank the staff, particularly Dr. Craig Ogata, of the Howard Hughes Medical Institute beamline (X4A) at the National Synchrotron Light Source at Brookhaven National Laboratory for invaluable support in collecting MAD data. We are also grateful to Debra Ehrgott and Li Su for help with data collection, Michael Burgess and James Pang for peptide synthesis, and Dr. Steven J. Gamblin for helpful suggestions. D. C. C. is supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. J. M. B. is a Whitehead Fellow and acknowledges support from the W. M. Keck Foundation. This work was funded by the Howard Hughes Medical Institute and utilized the W. M. Keck Foundation X-ray Crystallography Facility at the Whitehead Institute.", "abstract": "The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) consists of a complex of gp120 and gp41. gp120 determines viral tropism by binding to target-cell receptors, while gp41 mediates fusion between viral and cellular membranes. Previous studies identified an \u03b1-helical domain within gp41 composed of a trimer of two interacting peptides. The crystal structure of this complex, composed of the peptides N36 and C34, is a six-helical bundle. Three N36 helices form an interior, parallel coiled-coil trimer, while three C34 helices pack in an oblique, antiparallel manner into highly conserved, hydrophobic grooves on the surface of this trimer. This structure shows striking similarity to the low-pH-induced conformation of influenza hemagglutinin and likely represents the core of fusion-active gp41. Avenues for the design/discovery of small-molecule inhibitors of HIV infection are directly suggested by this structure.", "date": "1997-04-18", "date_type": "published", "publication": "Cell", "volume": "89", "number": "2", "publisher": "Elsevier", "pagerange": "263-273", "id_number": "CaltechAUTHORS:20170707-131349087", "issn": "0092-8674", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170707-131349087", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Jane Coffin Childs Memorial Fund for Medical Research" }, { "agency": "Whitehead Charitable Foundation" }, { "agency": "W. M. Keck Foundation" }, { "agency": "Howard Hughes Medical Institute (HHMI)" } ] }, "collection": "CaltechAUTHORS", "doi": "10.1016/S0092-8674(00)80205-6", "resource_type": "article", "pub_year": "1997", "author_list": "Chan, David C.; Fass, Deborah; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/04h8n-qpt19", "eprint_id": 29186, "eprint_status": "archive", "datestamp": "2023-08-20 06:21:23", "lastmod": "2023-10-24 18:25:24", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Wynshaw-Boris-A", "name": { "family": "Wynshaw-Boris", "given": "Anthony" } }, { "id": "Leder-P", "name": { "family": "Leder", "given": "Philip" } } ] }, "title": "Formin isoforms are differentially expressed in the mouse embryo and are required for normal expression of fgf-4 and shh in the limb bud", "ispublished": "pub", "full_text_status": "public", "keywords": "limb deformity, limb mutant, limb development,\npolarizing activity, apical ectodermal ridge, shh, fgf-4", "note": "\u00a9 1995 The Company of Biologists Limited.\nAccepted 20 June 1995.\nWe are grateful to A. Burke, P. Chambon, J. H\u00e9bert, G. Martin and\nA. McMahon for providing probes. We thank members of the Leder\nlaboratory for helpful suggestions throughout this project.\n\nPublished - CHAdev95b.pdf
", "abstract": "Mice homozygous for the recessive limb deformity (ld) mutation display both limb and renal defects. The limb defects, oligodactyly and syndactyly, have been traced to improper differentiation of the apical ectodermal ridge (AER) and shortening of the anteroposterior limb axis. The renal defects, usually aplasia, are thought to result from failure of ureteric bud outgrowth. Since the ld locus gives rise to multiple RNA isoforms encoding several different proteins (termed formins), we wished to understand their role in the formation of these organs. Therefore, we first examined the embryonic expression patterns of the four major ld mRNA isoforms. Isoforms I, II and III (all containing a basic amino terminus) are expressed in dorsal root ganglia, cranial ganglia and the developing kidney including the ureteric bud. Isoform IV (containing an acidic amino terminus) is expressed in the notochord, the somites, the apical ectodermal ridge (AER) of the limb bud and the developing kidney including the ureteric bud. Using a lacZ reporter assay in transgenic mice, we show that this differential expression of isoform IV results from distinct regulatory sequences upstream of its first exon. These expression patterns suggest that all four isoforms may be involved in ureteric bud outgrowth, while isoform IV may be involved in AER differentiation. To define further the developmental consequences of the ld limb defect, we analyzed the expression of a number of genes thought to play a role in limb development. Most significantly, we find that although the AERs of ld limb buds express several AER markers, they do not express detectable levels of fibroblast growth factor 4 (fgf-4), which has been proposed to be the AER signal to the mesoderm. Thus we conclude that one or more formins are necessary to initiate and/or maintain fgf-4 production in the distal limb. Since ld limbs form distal structures such as digits, we further conclude that while fgf-4 is capable of supporting distal limb outgrowth in manipulated limbs, it is not essential for distal outgrowth in normal limb development. In addition, ld limbs show a severe decrease in the expression of several mesodermal markers, including sonic hedgehog (shh), a marker for the polarizing region and Hoxd-12, a marker for posterior mesoderm. We propose that incomplete differentiation of the AER in ld limb buds leads to reduction of polarizing activity and defects along the anteroposterior axis.", "date": "1995-10", "date_type": "published", "publication": "Development", "volume": "121", "number": "10", "publisher": "Company of Biologists", "pagerange": "3151-3162", "id_number": "CaltechAUTHORS:20120208-082143624", "issn": "0950-1991", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120208-082143624", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "primary_object": { "basename": "CHAdev95b.pdf", "url": "https://authors.library.caltech.edu/records/04h8n-qpt19/files/CHAdev95b.pdf" }, "resource_type": "article", "pub_year": "1995", "author_list": "Chan, David C.; Wynshaw-Boris, Anthony; et el." }, { "id": "https://authors.library.caltech.eduhttps://authors.library.caltech.edu/records/aa1sg-ddk36", "eprint_id": 29185, "eprint_status": "archive", "datestamp": "2023-08-20 06:02:23", "lastmod": "2023-10-24 18:25:22", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chan-D-C", "name": { "family": "Chan", "given": "David C." }, "orcid": "0000-0002-0191-2154" }, { "id": "Laufer-E", "name": { "family": "Laufer", "given": "Ed" } }, { "id": "Tabin-C", "name": { "family": "Tabin", "given": "Cliff" } }, { "id": "Leder-P", "name": { "family": "Leder", "given": "Philip" } } ] }, "title": "Polydactylous limbs in Strong's Luxoid mice result from ectopic polarizing activity", "ispublished": "pub", "full_text_status": "public", "keywords": "Strong's Luxoid, limb mutant, limb development,\npolarizing activity, apical ectodermal ridge, mouse", "note": "\u00a9 1995 The Company of Biologists Limited.\nAccepted 21 March 1995.\nWe are grateful to Anne Burke, Andrew McMahon, and Gail\nMartin for providing probes. We thank members of the Leder and\nTabin labs for helpful advice and comments.\n\nPublished - CHAdev95a.pdf
", "abstract": "Strong's Luxoid (1st^D) is a semidominant mouse mutation in which heterozygotes show preaxial hindlimb polydactyly, and homozygotes show fore- and hindlimb polydactyly. The digit patterns of these polydactylous limbs resemble those caused by polarizing grafts, since additional digits with posterior character are present at the anterior side of the limb. Such observations suggest that 1st^D limb buds might contain a genetically determined ectopic region of polarizing activity. Accordingly, we show that mutant embryos ectopically express the pattern-determining genes fibroblast growth factor 4 (fgf-4), sonic hedgehog (shh), and Hoxd-12 in the anterior region of the limb. Further, we show that anterior mesoderm from mutant limbs exhibits polarizing activity when grafted into host chicken limbs. In contrast to an experimentally derived polydactylous transgenic mouse, forelimbs of homozygotes show a normal pattern of Hoxb-8 expression, indicating that the duplication of polarizing tissue here occurs downstream or independently of Hoxb-8. We suggest that the 1st gene product is involved in anteroposterior axis formation during normal limb development.", "date": "1995-07", "date_type": "published", "publication": "Development", "volume": "121", "number": "7", "publisher": "Company of Biologists", "pagerange": "1971-1978", "id_number": "CaltechAUTHORS:20120208-075531654", "issn": "0950-1991", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120208-075531654", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "primary_object": { "basename": "CHAdev95a.pdf", "url": "https://authors.library.caltech.edu/records/aa1sg-ddk36/files/CHAdev95a.pdf" }, "resource_type": "article", "pub_year": "1995", "author_list": "Chan, David C.; Laufer, Ed; et el." } ]