Elevating intracellular Na+ from 5 to 15 mmol/L in guinea pig cardiac myocytes accelerated mitochondrial Ca2+ decay and impaired energetic adaptation by partially oxidizing the NADH pool.
Mitochondrial Ca2+ (Ca2+m) regulates oxidative phosphorylation and thus contributes to energy supply and demand matching in cardiac myocytes. Mitochondria take up Ca2+ via the Ca2+ uniporter (MCU) and extrude it through the mitochondrial Na+/Ca2+ exchanger (mNCE). It is controversial whether mitochondria take up Ca2+ rapidly, on a beat-to-beat basis, or slowly, by temporally integrating cytosolic Ca2+ (Ca2+c) transients. Furthermore, although mitochondrial Ca2+ efflux is governed by mNCE, it is unknown whether elevated intracellular Na+ (Na+i) affects mitochondrial Ca2+ uptake and bioenergetics. To monitor Ca2+m, mitochondria of guinea pig cardiac myocytes were loaded with rhod-2-acetoxymethyl ester (rhod-2 AM), and Ca2+c was monitored with indo-1 after dialyzing rhod-2 out of the cytoplasm. Ca2+c transients, elicited by voltage-clamp depolarizations, were accompanied by fast Ca2+m transients, whose amplitude (delta) correlated linearly with deltaCa2+c. Under beta-adrenergic stimulation, Ca2+m decay was approximately 2.5-fold slower than that of Ca2+c, leading to diastolic accumulation of Ca2+m when amplitude or frequency of deltaCa2+c increased. The MCU blocker Ru360 reduced deltaCa2+m and increased deltaCa2+c, whereas the mNCE inhibitor CGP-37157 potentiated diastolic Ca2+m accumulation. Elevating Na+i from 5 to 15 mmol/L accelerated mitochondrial Ca2+ decay, thus decreasing systolic and diastolic Ca2+m. In response to gradual or abrupt changes of workload, reduced nicotinamide-adenine dinucleotide (NADH) levels were maintained at 5 mmol/L Na+i, but at 15 mmol/L, the NADH pool was partially oxidized. The results indicate that (1) mitochondria take up Ca2+ rapidly and contribute to fast buffering during a Ca2+c transient; and (2) elevated Na+i impairs mitochondrial Ca2+ uptake, with consequent effects on energy supply and demand matching. The latter effect may have implications for cardiac diseases with elevated Na+i.
Maack et al. (Fri,) reported a other. Elevated intracellular Na+ ([Na+]i) vs. 5 mmol/L [Na+]i was evaluated on Mitochondrial Ca2+ ([Ca2+]m) uptake and NADH levels. Elevating intracellular Na+ from 5 to 15 mmol/L in guinea pig cardiac myocytes accelerated mitochondrial Ca2+ decay and impaired energetic adaptation by partially oxidizing the NADH pool.