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

作者：Kohlhaas Michael; Maack Christoph^*

来源：Circulation, 2010, 122(22): 2273-2280.

DOI：10.1161/CIRCULATIONAHA.110.968057

• calcium
• heart failure
• ion channels
• metabolism
• sarcoplasmic reticulum

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,I-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,I-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. (Circulation. 2010;122:2273-2280.)

• 出版日期2010-11-30