Published online before print June 15, 2006, doi: 10.1161/01.RES.0000232546.92777.05
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Submitted on March 22, 2005
Revised on May 26, 2006
Accepted on June 7, 2006
Elevated Cytosolic Na+ Decreases Mitochondrial Ca2+ Uptake During Excitation-Contraction Coupling and Impairs Energetic Adaptation in Cardiac Myocytes
Christoph Maack ;
From the Johns Hopkins University, Institute of Molecular Cardiobiology, Division of Cardiology, Baltimore, Md. Current address for C.M.: Universität des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany.
* To whom correspondence should be addressed. E-mail: bor{at}jhmi.edu.
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-acetylmethyl 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 (
) correlated linearly with [Ca2+]c. Under 
-adrenergic stimulation, [Ca2+]m decay was 
2.5-fold slower than that of [Ca2+]c, leading to diastolic accumulation of [Ca2+]m when amplitude or frequency of [Ca2+]c increased. The MCU blocker Ru360 reduced [Ca2+]m and increased [Ca2+]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.
Key words: calcium uniporter • Na+/Ca2+ exchange • calcium buffer • energy metabolism • oxidative phosphorylation • Krebs cycle
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