187
views
0
recommends
+1 Recommend
1 collections
    40
    shares
      • Record: found
      • Abstract: found
      • Article: not found

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

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Author and article information

          Journal
          Nature
          Nature
          Springer Science and Business Media LLC
          1476-4687
          0028-0836
          Jun 19 2011
          : 476
          : 7360
          Affiliations
          [1 ] Department of Systems Biology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
          Article
          nature10234 NIHMS343036
          10.1038/nature10234
          3486726
          21685886
          f650667b-2911-4657-a3f9-ed973dc0e286
          History

          Comments

          Comment on this article