Proteolytic control of the mitochondrial calcium uniporter complex

Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4388-4393. doi: 10.1073/pnas.1702938114. Epub 2017 Apr 10.


The mitochondrial calcium uniporter is a Ca2+-activated Ca2+ channel complex mediating mitochondrial Ca2+ uptake, a process crucial for Ca2+ signaling, bioenergetics, and cell death. The uniporter is composed of the pore-forming MCU protein, the gatekeeping MICU1 and MICU2 subunits, and EMRE, a single-pass membrane protein that links MCU and MICU1 together. As a bridging subunit required for channel function, EMRE could paradoxically inhibit uniporter complex formation if expressed in excess. Here, we show that mitochondrial mAAA proteases AFG3L2 and SPG7 rapidly degrade unassembled EMRE using the energy of ATP hydrolysis. Once EMRE is incorporated into the complex, its turnover is inhibited >15-fold. Protease-resistant EMRE mutants produce uniporter subcomplexes that induce constitutive Ca2+ leakage into mitochondria, a condition linked to debilitating neuromuscular disorders in humans. The results highlight the dynamic nature of uniporter subunit assembly, which must be tightly regulated to ensure proper mitochondrial responses to intracellular Ca2+ signals.

Keywords: EMRE; MCU; mAAA protease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Signaling / physiology*
  • Gene Deletion
  • Gene Expression Regulation / physiology*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Peptide Hydrolases / metabolism
  • Protein Subunits


  • Calcium Channels
  • Protein Subunits
  • SMDT1 protein, human
  • mitochondrial calcium uniporter
  • Peptide Hydrolases
  • Calcium