title: Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter.
abstract: 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.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Baughman
authors.forename: Fabiana
authors.initials: F
authors.lastname: Perocchi
authors.forename: Hany S
authors.initials: HS
authors.lastname: Girgis
authors.forename: Molly
authors.initials: M
authors.lastname: Plovanich
authors.forename: Casey A
authors.initials: CA
authors.lastname: Belcher-Timme
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Sancak
authors.forename: X Robert
authors.initials: XR
authors.lastname: Bao
authors.forename: Laura
authors.initials: L
authors.lastname: Strittmatter
authors.forename: Olga
authors.initials: O
authors.lastname: Goldberger
authors.forename: Roman L
authors.initials: RL
authors.lastname: Bogorad
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D023281:Genomics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D017136:Ion Transport; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
chemical_list: D015220:Calcium Channels; D050505:Mutant Proteins; C034703:mitochondrial calcium uniporter; D002118:Calcium