MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca 2+ 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.