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

Publication date: 24 April 2018
Source:Cell Reports, Volume 23, Issue 4
Author(s): 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
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.

Graphical abstract

Teaser

Metazoan Ca²⁺ signal determines mitochondrial shape transition (MiST) and cellular quality control. Nemani et al. find that mitochondria undergo shape changes upon Ca²⁺ stress. MiST is distinct from matrix Ca²⁺-induced swelling and mitochondrial dynamics. The conserved Ca²⁺ sensor Miro1 enables MiST and promotes autophagy/mitophagy.


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