Enhancing Mitochondrial Ca 2+ Uptake in Myocytes From Failing Hearts Restores Energy Supply and Demand Matching

Mitochondrial ATP production is continually adjusted to energy demand through coordinated increases in oxidative phosphorylation and NADH production mediated by mitochondrial Ca2+(Ca2+m). Elevated cytosolic Na+ impairs Ca2+m accumulation during rapid pacing of myocytes, resulting in a decrease in NADH/NAD+ redox potential. Here, we determined 1) if accentuating Ca2+m accumulation prevents the impaired NADH response at high Na+i; 2) if Ca2+m handling and NADH/NAD+ balance during stimulation is impaired with heart failure (induced by aortic constriction); and 3) if inhibiting Ca2+m efflux improves NADH/NAD+ balance in heart failure. Ca2+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 Ca2+m transients and a rise in diastolic Ca2+m were observed during electric stimulation. Ca2+m accumulation was Na+i-dependent; less Ca2+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+/Ca2+ exchange inhibitor CGP-37157 (1 micromol/L) or raising cytosolic Pi (2 mmol/L) enhanced Ca2+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+/Ca2+ exchanger.