The mitochondrial Na+/Ca2+ exchanger-NCLX is an integrating hub for glucose dependent Na+ and Ca2+ signaling in pancreatic β cells

Although Na+ channels are abundantly expressed in β cells how Na+ fluxes are linked to glucose dependent Ca2+ signaling linked to pancreatic secretion is poorly underwood. Here we addressed the role of Na+ influx in regulating glucose dependent mitochondrial Ca2+ shuttling and cytosolic Ca2+ transients by fluorescently monitoring cytosolic and mitochondrial Na+ and Ca2+ transport in pancreatic b cells. Influx of Na+ via the TTX sensitive channels activated the mitochondrial Na+/Ca2+ exchanger NCLX, which in turn stimulated glucose dependent cytosolic Ca2+ influx. This effect was mimicked by pretreating cells with ouabain that by triggering cytosolic Na+accumulation eliminated the TTX dependent inhibition of mitochondrial and cytosolic Ca2+ signaling. Importantly knock down of NCLX expression by siNCLX eliminated the stimulatory effects of ouabain. Our results identify NCLX as the integrating hub for Na+ and Ca2+ signaling. Thus activation of the mitochondrial NCLX by Na+ influx accelerate mitochondrial Ca2+ shuttling and glucose dependent cytosolic Ca2+ rise in pancreatic β cells