NCLX is an essential component of mitochondrial Na + /Ca 2+ exchange

Abstract

Mitochondrial Ca 2+ efflux is linked to numerous cellular activities and pathophysiological processes. Although it is established that an Na + -dependent mechanism mediates mitochondrial Ca 2+ efflux, the molecular identity of this transporter has remained elusive. Here we show that the Na + /Ca 2+ exchanger NCLX is enriched in mitochondria, where it is localized to the cristae. Employing Ca 2+ and Na + fluorescent imaging, we demonstrate that mitochondrial Na + -dependent Ca 2+ efflux is enhanced upon overexpression of NCLX, is reduced by silencing of NCLX expression by siRNA, and is fully rescued by the concomitant expression of heterologous NCLX. NCLX-mediated mitochondrial Ca 2+ transport was inhibited, moreover, by CGP-37157 and exhibited Li + dependence, both hallmarks of mitochondrial Na + -dependent Ca 2+ efflux. Finally, NCLX-mediated mitochondrial Ca 2+ exchange is blocked in cells expressing a catalytically inactive NCLX mutant. Taken together, our results converge to the conclusion that NCLX is the long-sought mitochondrial Na + /Ca 2+ exchanger.