Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations

Cell Chem Biol. 2016 Sep 22;23(9):1157-1169. doi: 10.1016/j.chembiol.2016.07.012. Epub 2016 Aug 25.


Calcium (Ca(2+)) flux into the matrix is tightly controlled by the mitochondrial Ca(2+) uniporter (MCU) due to vital roles in cell death and bioenergetics. However, the precise atomic mechanisms of MCU regulation remain unclear. Here, we solved the crystal structure of the N-terminal matrix domain of human MCU, revealing a β-grasp-like fold with a cluster of negatively charged residues that interacts with divalent cations. Binding of Ca(2+) or Mg(2+) destabilizes and shifts the self-association equilibrium of the domain toward monomer. Mutational disruption of the acidic face weakens oligomerization of the isolated matrix domain and full-length human protein similar to cation binding and markedly decreases MCU activity. Moreover, mitochondrial Mg(2+) loading or blockade of mitochondrial Ca(2+) extrusion suppresses MCU Ca(2+)-uptake rates. Collectively, our data reveal that the β-grasp-like matrix region harbors an MCU-regulating acidic patch that inhibits human MCU activity in response to Mg(2+) and Ca(2+) binding.

Keywords: MCU-regulating acidic patch; autoinhibition; calcium binding; magnesium binding; mitochondrial calcium uniporter; oligomerization; stability; structure.

MeSH terms

  • Calcium / chemistry
  • Calcium / metabolism*
  • Calcium / pharmacology*
  • Calcium Channels / chemistry
  • Calcium Channels / metabolism*
  • Cations, Divalent / chemistry
  • Cations, Divalent / metabolism
  • Cations, Divalent / pharmacology
  • Humans
  • Magnesium / chemistry
  • Magnesium / metabolism*
  • Magnesium / pharmacology*
  • Models, Molecular
  • Protein Conformation / drug effects


  • Calcium Channels
  • Cations, Divalent
  • mitochondrial calcium uniporter
  • Magnesium
  • Calcium