MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics

Mitochondrial Ca2+ Uniporter (MCU)-dependent mitochondrial Ca2+ uptake is the primary mechanism for increasing matrix Ca2+ in most cell types. However, a limited understanding of the MCU complex assembly impedes the comprehension of the precise mechanisms underlying MCU activity. Here, we report that mouse cardiomyocytes and endothelial cells lacking MCU regulator 1 (MCUR1) have severely impaired [Ca2+]m uptake and IMCU current. MCUR1 binds to MCU and EMRE and function as a scaffold factor. Our protein binding analyses identified the minimal, highly conserved regions of coiled-coil domain of both MCU and MCUR1 that are necessary for heterooligomeric complex formation. Loss of MCUR1 perturbed MCU heterooligomeric complex and functions as a scaffold factor for the assembly of MCU complex. Vascular endothelial deletion of MCU and MCUR1 impaired mitochondrial bioenergetics, cell proliferation, and migration but elicited autophagy. These studies establish the existence of a MCU complex that assembles at the mitochondrial integral membrane and regulates Ca2+-dependent mitochondrial metabolism. [Display omitted] •MCUR1 binds to MCU and EMRE and functions as a scaffold factor•The coiled-coil domains of both MCU and MCUR1 are essential for MCU complex assembly•Genetic deletion of MCUR1 severely impairs [Ca2+]m uptake and IMCU current•MCUR1 deletion impairs bioenergetics and cell migration and elicits autophagy Tomar et al. show that genetic ablation of the MCU complex component MCUR1 perturbs MCU heterooligomeric complex and impairs mitochondrial Ca2+ uptake. MCUR1 binds to MCU and EMRE and functions as a scaffold factor that is necessary for proper Ca2+-dependent mitochondrial bioenergetics.