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Background— In heart failure, the Na+ -Ca2+ exchanger (NCX) is upregulated and mediates Ca2+ influx (instead of efflux) during the cardiac action potential. Although this partly compensates for impaired sarcoplasmic reticulum Ca2+ release and supports inotropy, the energetic consequences have never been considered. Because NCX-mediated Ca2+ influx is rather slow and mitochondrial Ca2+ uptake (which stimulates NADH production by the Krebs cycle) is thought to be facilitated by high Ca2+ gradients in a “mitochondrial Ca2+ microdomain,” we speculated that NCX-mediated Ca2+ influx negatively affects the bioenergetic feedback response.Methods and Results— With the use of a patch-clamp–based approach in guinea-pig myocytes, cytosolic and mitochondrial Ca2+ ([Ca2+ ]c and [Ca2+ ]m , respectively) was determined within the same cell after varying Ca2+ influx via L-type Ca2+ channels (I Ca,L ) or the NCX. The efficiency of mitochondrial Ca2+ uptake, indexed by the slope of plotting [Ca2+ ]m against [Ca2+ ]c during each Ca2+ transient, was maximal duringI Ca,L -triggered sarcoplasmic reticulum Ca2+ release. Depletion of sarcoplasmic reticulum Ca2+ load and increased contribution of the NCX to cytosolic Ca2+ influx independently reduced the efficiency of mitochondrial Ca2+ uptake. The upstroke velocity of cytosolic Ca2+ transients closely correlated with the efficiency of mitochondrial Ca2+ uptake. Despite comparable [Ca2+ ]c , sarcoplasmic reticulum Ca2+ release, but not NCX-mediated Ca2+ influx, led to stimulation of Ca2+ -sensitive dehydrogenases of the Krebs cycle.Conclusions— Increased contribution of the NCX to cytosolic Ca2+ transients, which occurs in cardiac myocytes from failing hearts, impairs mitochondrial Ca2+ uptake and the bioenergetic feedback response. This mechanism could contribute to energy starvation of failing hearts.

Adverse Bioenergetic Consequences of Na + -Ca 2+ Exchanger–Mediated Ca 2+ Influx in Cardiac Myocytes

Adverse Bioenergetic Consequences of Na ⁺ -Ca ²⁺ Exchanger–Mediated Ca ²⁺ Influx in Cardiac Myocytes