MCUR1 Is an Essential Component of Mitochondrial Ca2+ Uptake That Regulates Cellular Metabolism

Nat Cell Biol. 2012 Dec;14(12):1336-43. doi: 10.1038/ncb2622. Epub 2012 Nov 25.

Abstract

Ca(2+) flux across the mitochondrial inner membrane regulates bioenergetics, cytoplasmic Ca(2+) signals and activation of cell death pathways. Mitochondrial Ca(2+) uptake occurs at regions of close apposition with intracellular Ca(2+) release sites, driven by the inner membrane voltage generated by oxidative phosphorylation and mediated by a Ca(2+) selective ion channel (MiCa; ref. ) called the uniporter whose complete molecular identity remains unknown. Mitochondrial calcium uniporter (MCU) was recently identified as the likely ion-conducting pore. In addition, MICU1 was identified as a mitochondrial regulator of uniporter-mediated Ca(2+) uptake in HeLa cells. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Calcium / metabolism*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Cell Line
  • HeLa Cells
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*

Substances

  • Calcium Channels
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • MCUR1 protein, human
  • MICU1 protein, human
  • Membrane Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • mitochondrial calcium uniporter
  • Calcium