Ca2+-induced release of mitochondrial m-calpain from outer membrane with binding of calpain small subunit and Grp75

► Mitochondrial m-calpain large subunit localizes mainly in the mitochondrial outer membrane (OM). ► Free calpain small subunits are present in the mitochondrial intermembrane space. ► OM-bound calpains are activated by calpain small subunit, Grp75, and ATP. ► Free calpain small subunit releases the OM-bound m-calpain in the presence of Grp75, ATP, and Ca2+. ► Release of m-calpain from the OM has an important implication in facilitating apoptosis.