Extracellular calcium depletion transiently elevates oxygen consumption in neurosecretory PC12 cells through activation of mitochondrial Na+/Ca2+ exchange

Alexander V. Zhdanov, Manus W. Ward, Cormac T. Taylor, Ekaterina A. Souslova, Dmitri M. Chudakov, Jochen H.M. Prehn, Dmitri B. Papkovsky

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

Fluctuating extracellular Ca2+ regulates many aspects of neuronal (patho)physiology including cell metabolism and respiration. Using fluorescence-based intracellular oxygen sensing technique, we demonstrate that depletion of extracellular Ca2+ from 1.8 to ≤0.6mM by chelation with EGTA induces a marked spike in O2 consumption in differentiated PC12 cells. This respiratory response is associated with the reduction in cytosolic and mitochondrial Ca2+, minor depolarization on the mitochondrial membrane, moderate depolarization of plasma membrane, and no changes in NAD(P)H and ATP. The response is linked to the influx of extracellular Na+ and the subsequent activation of mitochondrial Na+/Ca2+ and Na+/H+ exchange. The mitochondrial Na+/Ca2+ exchanger (mNCX) activated by Na+ influx reduces Ca2+ and increases Na+ levels in the mitochondrial matrix. The excess of Na+ activates the mitochondrial Na+/H+ exchanger (NHE) increasing the outward pumping of protons, electron transport and O2 consumption. Reduction in extracellular Na+ and inhibition of Na+ influx through the receptor operated calcium channels and plasmalemmal NHE reduce the respiratory response. Inhibition of the mNCX, L-type voltage gated Ca2+ channels or the release of Ca2+ from the endoplasmic reticulum also reduces the respiratory spike, indicating that unimpaired intercompartmental Ca2+ exchange is critical for response development.

Original languageEnglish
Pages (from-to)1627-1637
Number of pages11
JournalBiochimica et Biophysica Acta - Bioenergetics
Volume1797
Issue number9
DOIs
Publication statusPublished - Sep 2010
Externally publishedYes

Keywords

  • Cell Metabolism
  • Extracellular calcium
  • Intracellular calcium
  • Mitochondria
  • Phosphorescent Oxygen-Sensitive Probe
  • Respiration

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