The mitochondrial Na+/Ca2+ exchanger upregulates glucose dependent Ca2+ signalling linked to insulin secretion

Mitochondria mediate dual metabolic and CA(2+) shuttling activities. While the former is required for CA(2+) signalling linked to Insulin secretion, the role of the latter in β cell function has not been well understood, primarily because the molecular identity of the mitochondrial CA(2+) transporters were elusive and the selectivity of their inhibitors was questionable. This study focuses on NCLX, the recently discovered mitochondrial Na(+)/CA(2+) exchanger that is linked to CA(2+) signalling in MIN6 and primary β cells. Suppression either of NCLX expression, using a siRNA construct (siNCLX) or of its activity, by a dominant negative construct (dnNCLX), enhanced mitochondrial CA(2+) influx and blocked efflux induced by glucose or by cell depolarization. In addition, NCLX regulated basal, but not glucose-dependent changes, in metabolic rate, mitochondrial membrane potential and mitochondrial resting CA(2+). Importantly, NCLX controlled the rate and amplitude of cytosolic CA(2+) changes induced by depolarization or high glucose, indicating that NCLX is a critical and rate limiting component in the cross talk between mitochondrial and plasma membrane CA(2+) signalling. Finally, knockdown of NCLX expression was followed by a delay in glucose-dependent Insulin secretion. These findings suggest that the mitochondrial Na(+)/CA(2+) exchanger, NCLX, shapes glucose-dependent mitochondrial and cytosolic CA(2+) signals thereby regulating the temporal pattern of Insulin secretion in β cells.