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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 (Δ) correlated linearly with Δ[Ca2+ ]c . Under β-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 Δ[Ca2+ ]c increased. The MCU blocker Ru360 reduced Δ[Ca2+ ]m and increased Δ[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 .

circulation research

Elevated Cytosolic Na <sup>+</sup> Decreases Mitochondrial Ca <sup>2+</sup> Uptake During Excitation-Contraction Coupling and Impairs Energetic Adaptation in Cardiac Myocytes

Elevated Cytosolic Na + Decreases Mitochondrial Ca 2+ Uptake During Excitation-Contraction Coupling and Impairs Energetic Adaptation in Cardiac Myocytes

Elevated Cytosolic Na ⁺ Decreases Mitochondrial Ca ²⁺ Uptake During Excitation-Contraction Coupling and Impairs Energetic Adaptation in Cardiac Myocytes