The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake

Cell Metab. 2015 Oct 6;22(4):721-33. doi: 10.1016/j.cmet.2015.08.019. Epub 2015 Sep 17.

Abstract

The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.

Keywords: CHCHD4; Ca(2+); MCUx; MICU; Mia40; disulfide; mitochondria; redox.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Calcium Channels / chemistry
  • Calcium Channels / metabolism*
  • Calcium-Binding Proteins / antagonists & inhibitors
  • Calcium-Binding Proteins / chemistry
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cation Transport Proteins / antagonists & inhibitors
  • Cation Transport Proteins / chemistry
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Dimerization
  • Disulfides / chemistry
  • Disulfides / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Ions / chemistry
  • Ions / metabolism
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / antagonists & inhibitors
  • Mitochondrial Membrane Transport Proteins / chemistry
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism

Substances

  • Calcium Channels
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • Disulfides
  • Ions
  • MIA40 protein, human
  • MICU1 protein, human
  • MICU2 protein, human
  • Mitochondrial Membrane Transport Proteins
  • RNA, Small Interfering
  • Calcium