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Journal Article
MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism
2012
Overview
The mitochondrial calcium uniporter (MCU) mediates calcium uptake by mitochondria and thus regulates cellular bioenergetics, but how MCU activity is modulated is not fully understood. Madesh, Foskett and colleagues report that the integral mitochondrial membrane protein MCUR1 (mitochondrial calcium uniporter regulator 1) binds to the MCU and promotes MCU-dependent calcium uptake to control ATP production and autophagy.
Ca
2+
flux across the mitochondrial inner membrane regulates bioenergetics, cytoplasmic Ca
2+
signals and activation of cell death pathways
1
,
2
,
3
,
4
,
5
,
6
,
7
,
8
,
9
,
10
,
11
. Mitochondrial Ca
2+
uptake occurs at regions of close apposition with intracellular Ca
2+
release sites
12
,
13
,
14
, driven by the inner membrane voltage generated by oxidative phosphorylation and mediated by a Ca
2+
selective ion channel (MiCa; ref.
15
) called the uniporter
16
,
17
,
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
,
22
. 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ ATP
/ Biology
/ Calcium
/ Calcium Channels - metabolism
/ Calcium-Binding Proteins - genetics
/ Calcium-Binding Proteins - metabolism
/ Cation Transport Proteins - genetics
/ Cation Transport Proteins - metabolism
/ Genes
/ Humans
/ Kinases
/ letter
/ Male
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Mice
/ Mitochondrial Membrane Transport Proteins - genetics
/ Mitochondrial Membrane Transport Proteins - metabolism
/ Mitochondrial Proteins - genetics
