MCUR1 is an Essential Component of Mitochondrial Ca ²⁺ Uptake that Regulates Cellular Metabolism

Abstract

Ca ²⁺ flux across the mitochondrial inner membrane regulates bioenergetics, cytoplasmic Ca ²⁺ signals and activation of cell death pathways ^{1– 11} . Mitochondrial Ca ²⁺ uptake occurs at regions of close apposition with intracellular Ca ²⁺ release sites ^{12– 14} , driven by the inner membrane voltage generated by oxidative phosphorylation and mediated by a Ca ²⁺ selective ion channel (MiCa ¹⁵ ) called the uniporter ^{16– 18} whose complete molecular identity remains unknown. Mitochondrial calcium uniporter (MCU) was recently identified as the likely ion-conducting pore ^{19, 20} . In addition, MICU1 was identified as a mitochondrial regulator of uniporter-mediated Ca ²⁺ uptake in HeLa cells ²¹ . 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.