Adverse Bioenergetic Consequences of Na+-Ca2+ Exchanger-Mediated Ca2+ Influx in Cardiac Myocytes

• Published in: Circulation (New York, N.Y.) N.Y.), 2010-11, Vol.122 (22), p.2273-2280
• Main Authors: KOHLHAAS, Michael, MAACK, Christoph
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood and lymphatic vessels; Calcium - metabolism; Calcium Channels, L-Type - metabolism; Cardiology. Vascular system; Cytosol - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Energy Metabolism - physiology; Guinea Pigs; Medical sciences; Mitochondria, Heart - metabolism; Models, Animal; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Oxidation-Reduction; Patch-Clamp Techniques; Sarcoplasmic Reticulum - metabolism; Sodium-Calcium Exchanger - physiology; Tobacco, tobacco smoking; Toxicology
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/circulationaha.110.968057

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 during I(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.