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.