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.
Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Iulia I
II
Nita
Michal
M
Hershfinkel
Daniel
D
Fishman
Eyal
E
Ozeri
Guy A
GA
Rutter
Stefano L
SL
Sensi
Daniel
D
Khananshvili
Eli C
EC
Lewis
Israel
I
Sekler
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D008928:Mitochondria; D015398:Signal Transduction / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; D019831:Sodium-Calcium Exchanger; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium