Pancreatic β-cell Na+ channels control global Ca 2+ signaling and oxidative metabolism by inducing Na+and Ca2+ responses that are propagated into mitochondria

Iulia I. Nita, Michal Hershfinkel, Chase Kantor, Guy A. Rutter, Eli Lewis, Israel Sekler

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Communication between the plasma membrane and mitochondria is essential for initiating the Ca2+ and metabolic signals required for secretion in β cells. Although voltage-dependent Na+ channels are abundantly expressed in β cells and activated by glucose, their role in communicating with mitochondria is unresolved. Here, we combined fluorescent Na+, Ca2+, and ATP imaging, electrophysiological analysis with tetrodotoxin (TTX)-dependent block of the Na+ channel, and molecular manipulation of mitochondrial Ca2+ transporters to study the communication between Na+ channels and mitochondria. We show that TTX inhibits glucose-dependent depolarization and blocks cytosolic Na+ and Ca2+ responses and their propagation into mitochondria. TTX-sensitive mitochondrial Ca2+ influx was largely blocked by knockdown of the mitochondrial Ca2+ uniporter (MCU) expression. Knockdown of the mitochondrial Na+/Ca2+ exchanger (NCLX) and Na+ dose response analysis demonstrated that NCLX mediates the mitochondrial Na+ influx and is tuned to sense the TTX-sensitive cytosolic Na+ responses. Finally, TTX blocked glucose-dependent mitochondrial Ca2+ rise, mitochondrial metabolic activity, and ATP production. Our results show that communication of the Na+ channels with mitochondria shape both global Ca2+ and metabolism signals linked to insulin secretion in β cells.

Original languageEnglish
Pages (from-to)3301-3312
Number of pages12
JournalFASEB Journal
Volume28
Issue number8
DOIs
StatePublished - 1 Jan 2014

Keywords

  • MCU
  • NCLX
  • TTX

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