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

Abstract

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.

• Authors: Ting Liu, Brian O'Rourke
• Journal: Circulation research (Circ Res) Vol. 103 Issue 3 Pg. 279-88 (Aug 01 2008) ISSN: 1524-4571 [Electronic] United States
• PMID: 18599868 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Sodium-Calcium Exchanger
• NAD
• Sodium
• Calcium

Topics

• Animals
• Biological Transport
• Calcium (metabolism)
• Disease Models, Animal
• Electrophysiology
• Energy Metabolism (physiology)
• Guinea Pigs
• Heart Failure
• Mitochondria, Heart (metabolism)
• Myocytes, Cardiac (metabolism, physiology)
• NAD (metabolism)
• Sodium (analysis)
• Sodium-Calcium Exchanger (antagonists & inhibitors)