SLP-2 negatively modulates mitochondrial sodium-calcium exchange

Mitochondria play a major role in cellular calcium homeostasis. Despite decades of studies, the molecules that mediate and regulate the transport of calcium ions in and out of the mitochondrial matrix remain unknown. Here, we investigate whether SLP-2, an inner membrane mitochondrial protein of unknown function, modulates the activity of mitochondrial Ca2+ transporters. In HeLa cells depleted of SLP-2, the amplitude and duration of mitochondrial Ca2+ elevations evoked by agonists were decreased compared to control cells. SLP-2 depletion increased the rates of calcium extrusion from mitochondria. This effect disappeared upon Na+ removal or addition of CGP-37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, and persisted in permeabilized cells exposed to a fixed cytosolic Na+ and Ca2+ concentration. The rates of mitochondrial Ca2+ extrusion were prolonged in SLP-2 over-expressing cells, independently of the amplitude of mitochondrial Ca2+ elevations. The amplitude of cytosolic Ca2+ elevations was increased by SLP-2 depletion and decreased by SLP-2 over-expression. These data show that SLP-2 modulates mitochondrial calcium extrusion, thereby altering the ability of mitochondria to buffer Ca2+ and to shape cytosolic Ca2+ signals.