Calcium regulation of mitochondrial carriers

Biochim Biophys Acta. 2016 Oct;1863(10):2413-21. doi: 10.1016/j.bbamcr.2016.03.024. Epub 2016 Mar 28.


Mitochondrial function is regulated by calcium. In addition to the long known effects of matrix Ca(2+), regulation of metabolite transport by extramitochondrial Ca(2+) represents an alternative Ca(2+)-dependent mechanism to regulate mitochondrial function. The Ca(2+) regulated mitochondrial transporters (CaMCs) are well suited for that role, as they contain long N-terminal extensions harboring EF-hand Ca(2+) binding domains facing the intermembrane space. They fall in two groups, the aspartate/glutamate exchangers, AGCs, major components of the NADH malate aspartate shuttle (MAS) and urea cycle, and the ATP-Mg(2+)/Pi exchangers or short CaMCs (APCs or SCaMCs). The AGCs are activated by relatively low Ca(2+) levels only slightly higher than resting Ca(2+), whereas all SCaMCs studied so far require strong Ca(2+) signals, above micromolar, for activation. In addition, AGCs are not strictly Ca(2+) dependent, being active even in Ca(2+)-free conditions. Thus, AGCs are well suited to respond to small Ca(2+) signals and that do not reach mitochondria. In contrast, ATP-Mg(2+)/Pi carriers are inactive in Ca(2+) free conditions and activation requires Ca(2+) signals that will also activate the calcium uniporter (MCU). By changing the net content of adenine nucleotides of the matrix upon activation, SCaMCs regulate the activity of the permeability transition pore, and the Ca(2+) retention capacity of mitochondria (CRC), two functions synergizing with those of the MCU. The different Ca(2+) activation properties of the two CaMCs are discussed in relation to their newly obtained structures. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Keywords: ATP-Mg(2+)/Pi carriers; Aspartate/glutamate carriers; Calcium; Mitochondrial carriers; Solute transport.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antiporters / physiology
  • Arabidopsis Proteins / metabolism
  • Biological Transport, Active
  • Calcium / physiology*
  • Calcium Signaling / physiology*
  • Calcium-Binding Proteins / physiology
  • Cell Respiration
  • Humans
  • Ion Transport
  • Mammals / metabolism
  • Mitochondrial Membrane Transport Proteins / deficiency
  • Mitochondrial Membrane Transport Proteins / physiology*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / physiology
  • Models, Molecular
  • Organic Anion Transporters / physiology
  • Protein Conformation
  • Saccharomyces cerevisiae Proteins / metabolism


  • ATP-Mg-Pi carrier proteins, mitochondria
  • Antiporters
  • Arabidopsis Proteins
  • Calcium-Binding Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Organic Anion Transporters
  • SLC25A12 protein, human
  • Saccharomyces cerevisiae Proteins
  • citrin
  • Calcium