Enhancing mitochondrial Ca2+ uptake in myocytes from failing hearts restores energy supply and demand matching

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondrial ATP production is continually adjusted to energy demand through coordinated increases in oxidative phosphorylation and NADH production mediated by mitochondrial Ca([Ca]m). Elevated cytosolic Na impairs [Ca]m accumulation during rapid pacing of myocytes, resulting in a decrease in NADH/NAD redox potential. Here, we determined 1) if accentuating [Ca]m accumulation prevents the impaired NADH response at high [Na]i; 2) if [Ca]m handling and NADH/NAD balance during stimulation is impaired with heart failure (induced by aortic constriction); and 3) if inhibiting [Ca]m efflux improves NADH/NAD balance in heart failure. [Ca]m and NADH were recorded in cells at rest and during voltage clamp stimulation (4Hz) with either 5 or 15 mmol/L [Na]i. Fast [Ca]m transients and a rise in diastolic [Ca]m were observed during electric stimulation. [Ca]m accumulation was [Na]i-dependent; less [Ca]m accumulated in cells with 15 Na versus 5 mmol/L Na and NADH oxidation was evident at 15 mmol/L Na, but not at 5 mmol/L Na. Treatment with either the mitochondrial Na/Ca exchange inhibitor CGP-37157 (1 μmol/L) or raising cytosolic Pi (2 mmol/L) enhanced [Ca]m accumulation and prevented the NADH oxidation at 15 mmol/L [Na]i. In heart failure myocytes, resting [Na]i increased from 5.2±1.4 to 16.8±3.1mmol/L and net NADH oxidation was observed during pacing, whereas NADH was well matched in controls. Treatment with CGP-37157 or lowering [Na]i prevented the impaired NADH response in heart failure. We conclude that high [Na]i (at levels observed in heart failure) has detrimental effects on mitochondrial bioenergetics, and this impairment can be prevented by inhibiting the mitochondrial Na/Ca exchanger.

Original languageEnglish (US)
Pages (from-to)279-288
Number of pages10
JournalCirculation research
Volume103
Issue number3
DOIs
StatePublished - Aug 1 2008

Keywords

  • /Ca2
  • Energy metabolism
  • Exchanger
  • Excitation-contraction coupling
  • Heart failure
  • Ion transport
  • Na
  • Oxidative phosphorylation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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