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
