Abstract
Mitochondrial Ca(2+) Uniporter (MCU)-dependent mitochondrial Ca(2+) uptake is the primary mechanism for increasing matrix Ca(2+) 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 [Ca(2+)]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 Ca(2+)-dependent mitochondrial metabolism.
Highlights
The mitochondrial Ca2+ uniporter (MCU) is a multimeric complex that mediates the rapid uptake of cytosolic Ca2+ from intracellular store release
Deletion of MCU regulator 1 (MCUR1) in the Heart and Vasculature Regulates MCU-Dependent [Ca2+]m Uptake To investigate the regulatory role of MCUR1 in MCU-mediated [Ca2+]m uptake in vivo, we generated tissue-specific MCUR1 null mice
We investigated MCU- and MCUR1-interacting domains that are required for MCU complex assembly
Summary
The mitochondrial Ca2+ uniporter (MCU) is a multimeric complex that mediates the rapid uptake of cytosolic Ca2+ from intracellular store release. MCU is a highly selective Ca2+ channel, the precise physiological role and the molecular structure of the mitochondrial Ca2+ uniporter complex still has to be determined (Kamer and Mootha, 2015; Kirichok et al, 2004). The defining feature of MCU as a channel is that it is activated by finite cytosolic Ca2+ ([Ca2+]c) and driven by mitochondrial membrane potential (DJm) and pH (Csordas et al, 2013; Gunter and Pfeiffer, 1990; Mallilankaraman et al, 2012b; Nicholls, 2005; Santo-Domingo and Demaurex, 2012). Given that the discovery of MCU and its regulators MICU1, MICU2
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