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

Ca²⁺ flux across the mitochondrial inner membrane regulates bioenergetics, cytoplasmic Ca²⁺ signals and activation of cell death pathways. Mitochondrial Ca²⁺ uptake occurs at regions of close apposition with intracellular Ca²⁺ release sites, driven by the inner membrane voltage generated by oxidative phosphorylation and mediated by a Ca²⁺ 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 Ca²⁺ uptake. MCUR1 binds to MCU and regulates ruthenium-red-sensitive MCU-dependent Ca²⁺ uptake. MCUR1 knockdown does not alter MCU localization, but abrogates Ca²⁺ 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 Ca²⁺ uptake and maintenance of normal cellular bioenergetics.