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 language | English (US) |
---|---|
Pages (from-to) | 279-288 |
Number of pages | 10 |
Journal | Circulation research |
Volume | 103 |
Issue number | 3 |
DOIs | |
State | Published - 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