The Mitochondrial Na ⁺/Ca ²⁺ Exchanger Upregulates Glucose Dependent Ca ²⁺ 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.