Abstract
Mitochondria shape cytosolic calcium ([Ca(2+)](c)) transients and utilize the mitochondrial Ca(2+) ([Ca(2+)](m)) in exchange for bioenergetics output. Conversely, dysregulated [Ca(2+)](c) causes [Ca(2+)](m) overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca(2+) uptake exhibited elevated [Ca(2+)](c) and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca(2+)-induced shape change that is distinct from mitochondrial fission and swelling. [Ca(2+)](c) elevation, but not MCU-mediated Ca(2+) 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, Ca(2+)-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 Ca(2+) sensor that decodes metazoan Ca(2+) signals as MiST.