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

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

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

Authors: Nemani N, Carvalho E, Tomar D, Dong Z, Ketschek A, Breves SL, Jaña F, Worth AM, Heffler J, Palaniappan P, Tripathi A, Subbiah R, Riitano MF, Seelam A, Manfred T, Itoh K, Meng S, Sesaki H, Craigen WJ, Rajan S, Shanmughapriya S, Caplan J, Prosser BL, Gill DL, Stathopulos PB, Gallo G, Chan DC, Mishra P, Madesh M

Abstract
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.

PMID: 29694881 [PubMed - in process]

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