Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter

By Joshua M. Baughman, F. Perocchi, Hany S. Girgis, Molly E. Plovanich, Casey A. Belcher-Timme, Y. Sancak, X. Robert Bao, Laura Strittmatter, O. Goldberger, R. Bogorad and 3 more. Nature, 2011

1,879 citations recorded by the source corpus.

Mitochondria from diverse organisms are capable of transporting large amounts of Ca2+ via a ruthenium-red-sensitive, membrane-potential-dependent mechanism called the uniporter. Although the uniporter’s biophysical properties have been studied extensively, its molecular composition remains elusive. We recently used comparative proteomics to identify MICU1 (also known as CBARA1), an EF-hand-containing protein that serves as a putative regulator of the uniporter. Here, we use whole-genome phylogenetic profiling, genome-wide RNA co-expression analysis and organelle-wide protein coexpression analysis to predict proteins functionally related to MICU1. All three methods converge on a novel predicted transmembrane protein, CCDC109A, that we now call ‘mitochondrial calcium uniporter’ (MCU). MCU forms oligomers in the mitochondrial inner membrane, physically interacts with MICU1, and resides within a large molecular weight complex. Silencing MCU in cultured cells or in vivo in mouse liver severely abrogates mitochondrial Ca2+ uptake, whereas mitochondrial respiration and membrane potential remain fully intact. MCU has two predicted transmembrane helices, which are separated by a highly conserved linker facing the intermembrane space. Acidic residues in this linker are required for its full activity. However, an S259A point mutation retains function but confers resistance to Ru360, the most potent inhibitor of the uniporter. Our genomic, physiological, biochemical and pharmacological data firmly establish MCU as an essential component of the mitochondrial Ca2+ uniporter.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/721641b1ad754c7b0e0c9974882868e2c5503c69

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Citations in the corpus

Mitochondrial dysfunction in pathophysiology of heart failure (2018, background): “One major player in the control of mitochondrial Ca2+ uptake is the recently identified mitochondrial Ca2+ uniporter (MCU) complex (13, 14).”
MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins (2015, methodology): “0 has been widely used to elucidate the function of uncharacterized genes and pathways (6–9), including reverse genetic screens (8,10) and forward genetic approaches to identify genes underlying rare mitochondrial disorders (11–14).”
Role of Mitochondrial Ca2+ in the Regulation of Cellular Energetics (2012, background): “Finally, the transporters for Ca2+ across the mitochondrial membrane have just recently been identified (24;25) almost 50 years after the description of Ca2+ uptake by mitochondria(26).”
Engineered ascorbate peroxidase as a genetically-encoded reporter for electron microscopy (2012, background): “(3) COS-7 cells expressing APEX fusion to histone 2B.”
Initiation and perpetuation of NLRP3 inflammasome activation and assembly (2015, background): “Triantafilou et al. (85) showed that MCU is required for complement membrane attack complexinduced NLRP3 inflammasome activation.”
Mitochondria: In Sickness and in Health (2012, background): “…adenosine monophosphate; ATP, adenosine triphosphate; Ac, acetyl group. participate in Ca2+ homeostasis, shaping the spatiotemporal distribution of this second messenger by buffering Ca2+ flux from the plasma membrane and endoplasmic reticulum (ER) (Baughman et al., 2011; De Stefani et al., 2011).”