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(Circulation Research. 2006;99:172.)
© 2006 American Heart Association, Inc.

Cellular Biology

Elevated Cytosolic Na⁺ Decreases Mitochondrial Ca²⁺ Uptake During Excitation-Contraction Coupling and Impairs Energetic Adaptation in Cardiac Myocytes

Christoph Maack, Sonia Cortassa, Miguel A. Aon, Anand N. Ganesan, Ting Liu, Brian O’Rourke

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.

Correspondence to Brian O’Rourke, PhD, Institute of Molecular Cardiobiology, Division of Cardiology, 720 Rutland Ave, 1059 Ross Bldg, Baltimore, MD 21205-2195. 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–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 () correlated linearly with [Ca²⁺]_c. Under ß-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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