Solute carrier 41A3 encodes for a mitochondrial Mg 2+ efflux system

The important role of magnesium (Mg 2+ ) in normal cellular physiology requires flexible, yet tightly regulated, intracellular Mg 2+ homeostasis (IMH). However, only little is known about Mg 2+ transporters of subcellular compartments such as mitochondria, despite their obvious importance for the deposition and reposition of intracellular Mg 2+ pools. In particular, knowledge about mechanisms responsible for extrusion of Mg 2+ from mitochondria is lacking. Based on circumstantial evidence, two possible mechanisms of Mg 2+ release from mitochondria were predicted: (1) Mg 2+ efflux coupled to ATP translocation via the ATP-Mg/Pi carrier and (2) Mg 2+ efflux via a H + /Mg 2+ exchanger. Regardless, the identity of the H + -coupled Mg 2+ efflux system is unknown. We demonstrate here that member A3 of solute carrier (SLC) family 41 is a mitochondrial Mg 2+ efflux system. Mitochondria of HEK293 cells overexpressing SLC41A3 exhibit a 60% increase in the extrusion of Mg 2+ compared with control cells. This efflux mechanism is Na + -dependent and temperature sensitive. Our data identify SLC41A3 as the first mammalian mitochondrial Mg 2+ efflux system, which greatly enhances our understanding of intracellular Mg 2+ homeostasis.