Mitochondrial calcium ion transport

Stable Identifier
R-HSA-8949215
Type
Pathway
Species
Homo sapiens
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Divalent calcium ions (Ca2+) are transported from the cytosol into the mitochondrial matrix and back out of the matrix into the cytosol (reviewed in Santo-Domingo et al. 2010, De Stefani et al. 2016). In the matrix, Ca2+ binds and allosterically regulates pyruvate dehydrogenase, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase, and possibly other enzymes (Rizzuto et al. 2012). Matrix calcium is also observed to regulate release of caspase cofactors and calcium flux through channels on neighboring membranes, The pathway into the mitochondrion involves VDAC1, VDAC2, and VDAC3 in the outer membrane and the mitochondrial calcium uniporter (MCU) complex in the inner membrane. VDACs in the open conformation are anion channels. However in the closed conformation they transport Ca2+ from the cytosol to the intermembrane space. When calcium concentrations in the cytosol and intermembrane space are high, the MCU complex opens and transports Ca2+ from the intermembrane space to the mitochondrial matrix using the driving force of the membrane potential (reviewed in Drago et al. 2011, Marchi et al. 2014, De Stefani et al. 2015).
Efflux of Ca2+ from the matrix to the intermembrane space is catalyzed by the Na+/Ca2+ antiporter SLC8B1 (NCLX) located in the inner membrane. LETM1 is also observed to export calcium from the matrix to the intermembrane space by acting as an H+/Ca2+ antiporter, although somewhat contradictory results have been found in knockdowns of LETM1. Calcium in the intermembrane space may be transported to the cytosol by the Na+/Ca2+ antiporter SLC8A3 (NCX3), however the mitochondrial localization of SLC8A3 is controversial and SLC8A3 has a limited distribution among tissues.

Literature References
PubMed ID Title Journal Year
21934651 After half a century mitochondrial calcium in- and efflux machineries reveal themselves

Drago, I, Pizzo, P, Pozzan, T

EMBO J. 2011
24366263 The mitochondrial calcium uniporter complex: molecular components, structure and physiopathological implications

Marchi, S, Pinton, P

J. Physiol. (Lond.) 2014
20079335 Calcium uptake mechanisms of mitochondria

Santo-Domingo, J, Demaurex, N

Biochim. Biophys. Acta 2010
22850819 Mitochondria as sensors and regulators of calcium signalling

Rizzuto, R, De Stefani, D, Raffaello, A, Mammucari, C

Nat. Rev. Mol. Cell Biol. 2012
25463276 The mitochondrial Ca(2+) uniporter complex

Foskett, JK, Philipson, B

J. Mol. Cell. Cardiol. 2015
25896525 Structure and function of the mitochondrial calcium uniporter complex

De Stefani, D, Patron, M, Rizzuto, R

Biochim. Biophys. Acta 2015
27145841 Enjoy the Trip: Calcium in Mitochondria Back and Forth

De Stefani, D, Rizzuto, R, Pozzan, T

Annu. Rev. Biochem. 2016
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