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Nature DOI:10.1038/nature10234

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

Publication TypeJournal Article
Year of Publication2011
AuthorsBaughman, JM, Perocchi, F, Girgis, HS, Plovanich, M, Belcher-Timme, CA, Sancak, Y, X Bao, R, Strittmatter, L, Goldberger, O, Bogorad, RL, Koteliansky, V, Mootha, VK
Date Published2011 Jun 19
KeywordsAmino Acid Sequence, Animals, Calcium, Calcium Channels, Genomics, HEK293 Cells, HeLa Cells, Humans, Ion Transport, Mice, Mitochondria, Liver, Mitochondrial Membranes, Molecular Sequence Data, Mutant Proteins, Phylogeny, Protein Structure, Quaternary, Protein Structure, Tertiary

Mitochondria from diverse organisms are capable of transporting large amounts of Ca(2+) 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 Ca(2+) 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 Ca(2+) uniporter.


Alternate JournalNature
PubMed ID21685886
PubMed Central IDPMC3486726
Grant ListGM0077465 / GM / NIGMS NIH HHS / United States
R24 DK080261 / DK / NIDDK NIH HHS / United States
R01 GM077465-01A1 / GM / NIGMS NIH HHS / United States
DK080261 / DK / NIDDK NIH HHS / United States
R01 GM077465 / GM / NIGMS NIH HHS / United States