The Ca2+-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca2+ Uptake

Summary The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca 2+ signaling. Among the interaction partners of Mia40 is MICU1—the regulator of the mitochondrial Ca 2+ uniporter (MCU), which transfers Ca 2+ across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca 2+ uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca 2+ levels: the dimer associates with MCU at low levels of Ca 2+ and dissociates upon high Ca 2+ concentrations. Our findings support a model in which mitochondrial Ca 2+ uptake is regulated by a Ca 2+ -dependent remodeling of the uniporter complex.