EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter

Cell Rep. 2016 Jan 26;14(3):403-410. doi: 10.1016/j.celrep.2015.12.054. Epub 2016 Jan 7.


The mitochondrial uniporter (MCU) is an ion channel that mediates Ca(2+) uptake into the matrix to regulate metabolism, cell death, and cytoplasmic Ca(2+) signaling. Matrix Ca(2+) concentration is similar to that in cytoplasm, despite an enormous driving force for entry, but the mechanisms that prevent mitochondrial Ca(2+) overload are unclear. Here, we show that MCU channel activity is governed by matrix Ca(2+) concentration through EMRE. Deletion or charge neutralization of its matrix-localized acidic C terminus abolishes matrix Ca(2+) inhibition of MCU Ca(2+) currents, resulting in MCU channel activation, enhanced mitochondrial Ca(2+) uptake, and constitutively elevated matrix Ca(2+) concentration. EMRE-dependent regulation of MCU channel activity requires intermembrane space-localized MICU1, MICU2, and cytoplasmic Ca(2+). Thus, mitochondria are protected from Ca(2+) depletion and Ca(2+) overload by a unique molecular complex that involves Ca(2+) sensors on both sides of the inner mitochondrial membrane, coupled through EMRE.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Calcium / metabolism*
  • Calcium Channels / chemistry
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium-Binding Proteins / antagonists & inhibitors
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cation Transport Proteins / antagonists & inhibitors
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Cytoplasm / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Potential, Mitochondrial
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / antagonists & inhibitors
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Patch-Clamp Techniques
  • RNA Interference
  • RNA, Small Interfering / metabolism


  • Calcium Channels
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • MICU1 protein, human
  • MICU2 protein, human
  • Mitochondrial Membrane Transport Proteins
  • RNA, Small Interfering
  • SMDT1 protein, human
  • Calcium