title: 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.affiliation: Division of Cardiology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D004594:Electrophysiology; D004734:Energy Metabolism / Q000502:physiology*; D006168:Guinea Pigs; D006333:Heart Failure; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D009243:NAD / Q000378:metabolism; D012964:Sodium / Q000032:analysis; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors
chemical_list: D019831:Sodium-Calcium Exchanger; D009243:NAD; D012964:Sodium; D002118:Calcium