Abstract

Mitochondria shape cytosolic calcium ([Ca2+](c)) tran-sients and utilize the mitochondrial Ca2+ ([Ca2+](m)) in exchange for bioenergetics output. Conversely, dys-regulated [Ca2+](c) causes [Ca2+](m) overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca2+ 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 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 mito-chondrial 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 auto-phagy/mitophagy that is attenuated in Miro1 EF1 mutants. Thus, Miro1 is a cytosolic Ca2+ sensor that decodes metazoan Ca2+ signals as MiST.