MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism

CA(2+) flux across the mitochondrial inner membrane regulates bioenergetics, cytoplasmic CA(2+) signals and activation of cell death pathways. Mitochondrial CA(2+) uptake occurs at regions of close apposition with intracellular CA(2+) release sites, driven by the inner membrane voltage generated by Oxidative Phosphorylation and mediated by a CA(2+) selective ion channel (MiCa; ref. ) called the uniporter whose complete molecular identity remains unknown. Mitochondrial calcium uniporter (MCU) was recently identified as the likely ion-conducting pore. In addition, MICU1 was identified as a mitochondrial regulator of uniporter-mediated CA(2+) uptake in HeLa cells. Here we identified CCDC90A, hereafter referred to as MCUR1 (mitochondrial calcium uniporter regulator 1), an integral membrane protein required for MCU-dependent mitochondrial CA(2+) uptake. MCUR1 binds to MCU and regulates ruthenium-red-sensitive MCU-dependent CA(2+) uptake. MCUR1 knockdown does not alter MCU localization, but abrogates CA(2+) uptake by energized mitochondria in intact and permeabilized cells. Ablation of MCUR1 disrupts Oxidative Phosphorylation, lowers cellular ATP and activates AMP kinase-dependent pro-survival Autophagy. Thus, MCUR1 is a critical component of a mitochondrial uniporter channel complex required for mitochondrial CA(2+) uptake and maintenance of normal cellular bioenergetics.