MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress.

Mitochondria shape cytosolic calcium ([Ca2+]c) transients and utilize the mitochondrial Ca2+ ([Ca2+]m) in exchange for bioenergetics output. Conversely, dysregulated [Ca2+]c causes [Ca2+]m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca2+ uptake exhibited elevated [Ca2+]c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca2+-induced shape change that is distinct from mitochondrial fission and swelling. [Ca2+]c elevation, but not MCU-mediated Ca2+ 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, Ca2+-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 Ca2+ sensor that decodes metazoan Ca2+ signals as MiST. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

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. 2018 Apr 24;23(4):1005-1019

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PMID: 29694881

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