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MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca^(2+) Stress

Nemani, Neeharika and Carvalho, Edmund and Tomar, Dhanendra and Dong, Zhiwei and Ketschek, Andrea and Breves, Sarah L. and Jaña, Fabián and Worth, Alison M. and Heffler, Julie and Palaniappan, Palaniappan and Tripathi, Aparna and Subbiah, Ramasamy and Riitano, Massimo F. and Seelam, Ajay and Manfred, Thomas and Itoh, Kie and Meng, Shuxia and Sesaki, Hiromi and Craigen, William J. and Rajan, Sudarsan and Shanmughapriya, Santhanam and Caplan, Jeffrey and Prosser, Benjamin L. and Gill, Donald L. and Stathopulos, Peter B. and Gallo, Gianluca and Chan, David C. and Mishra, Prashant and Madesh, Muniswamy (2018) MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca^(2+) Stress. Cell Reports, 23 (4). pp. 1005-1019. ISSN 2211-1247. PMCID PMC5973819.

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[img] Video (MPEG) (Video S4. Ca2+ Sensor Miro1 Triggers MiST, Related to Figure 5) - Supplemental Material
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[img] Video (MPEG) (Video S5. Miro1 EF Hand 1 Determines MiST, Related to Figure 5) - Supplemental Material
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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.

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Chan, David C.0000-0002-0191-2154
Alternate Title:MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca 2+ Stress
Additional Information:© 2018 The Author(s). Open Access funded by National Institutes of Health. Under a Creative Commons license (CC-BY 4.0) Received 13 March 2017, Revised 22 February 2018, Accepted 21 March 2018, Available online 25 April 2018. We thank Craig B. Thompson, Richard Youle, Gia Voeltz, Tom Rapoport, and Gary Yellen for sharing Bax^(−/−)Bak^(−/−) MEFs, mito-Keima, mito-BFP, sec61-β, 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). Author 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. The authors declare no competing interests.
Funding AgencyGrant Number
NIHR01 NS095471
American Heart Association17PRE33660720
American Heart Association17POST33660251
China Scholarship Council201403170252
Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT)3140458
NIHP20 GM103446
Subject Keywords:mitochondrial shape; MiST; calcium; Miro; EF hand; PTP; MCU; mitophagy; autophagy; mitochondrial dynamics
Issue or Number:4
PubMed Central ID:PMC5973819
Record Number:CaltechAUTHORS:20180425-144714424
Persistent URL:
Official Citation:Neeharika Nemani, Edmund Carvalho, Dhanendra Tomar, Zhiwei Dong, Andrea Ketschek, Sarah L. Breves, Fabián Jaña, Alison M. Worth, Julie Heffler, Palaniappan Palaniappan, Aparna Tripathi, Ramasamy Subbiah, Massimo F. Riitano, Ajay Seelam, Thomas Manfred, Kie Itoh, Shuxia Meng, Hiromi Sesaki, William J. Craigen, Sudarsan Rajan, Santhanam Shanmughapriya, Jeffrey Caplan, Benjamin L. Prosser, Donald L. Gill, Peter B. Stathopulos, Gianluca Gallo, David C. Chan, Prashant Mishra, Muniswamy Madesh, MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress, Cell Reports, Volume 23, Issue 4, 24 April 2018, Pages 1005-1019, ISSN 2211-1247, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:86043
Deposited By: George Porter
Deposited On:25 Apr 2018 23:11
Last Modified:24 Feb 2020 10:30

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