The Mitochondrial Na +/Ca 2+ Exchanger Upregulates Glucose Dependent Ca 2+ Signalling Linked to Insulin Secretion

Iulia I. Nita, Michal Hershfinkel, Daniel Fishman, Eyal Ozeri, Guy A. Rutter, Stefano L. Sensi, Daniel Khananshvili, Eli C. Lewis, Israel Sekler

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere46649
JournalPLoS ONE
Volume7
Issue number10
DOIs
StatePublished - 8 Oct 2012

ASJC Scopus subject areas

  • General

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