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

M. Kohlhaas, C. Maack
2010 Circulation  
Background-In heart failure, the Na ϩ -Ca 2ϩ exchanger (NCX) is upregulated and mediates Ca 2ϩ influx (instead of efflux) during the cardiac action potential. Although this partly compensates for impaired sarcoplasmic reticulum Ca 2ϩ release and supports inotropy, the energetic consequences have never been considered. Because NCX-mediated Ca 2ϩ influx is rather slow and mitochondrial Ca 2ϩ uptake (which stimulates NADH production by the Krebs cycle) is thought to be facilitated by high Ca 2ϩ
more » ... ed by high Ca 2ϩ gradients in a "mitochondrial Ca 2ϩ microdomain," we speculated that NCX-mediated Ca 2ϩ 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 Ca 2ϩ ([Ca 2ϩ ] c and [Ca 2ϩ ] m , respectively) was determined within the same cell after varying Ca 2ϩ influx via L-type Ca 2ϩ channels (I Ca,L ) or the NCX. The efficiency of mitochondrial Ca 2ϩ uptake, indexed by the slope of plotting [Ca 2ϩ ] m against [Ca 2ϩ ] c during each Ca 2ϩ transient, was maximal during I Ca,L -triggered sarcoplasmic reticulum Ca 2ϩ release. Depletion of sarcoplasmic reticulum Ca 2ϩ load and increased contribution of the NCX to cytosolic Ca 2ϩ influx independently reduced the efficiency of mitochondrial Ca 2ϩ uptake. The upstroke velocity of cytosolic Ca 2ϩ transients closely correlated with the efficiency of mitochondrial Ca 2ϩ uptake. Despite comparable [Ca 2ϩ ] c , sarcoplasmic reticulum Ca 2ϩ release, but not NCX-mediated Ca 2ϩ influx, led to stimulation of Ca 2ϩ -sensitive dehydrogenases of the Krebs cycle. Conclusions-Increased contribution of the NCX to cytosolic Ca 2ϩ transients, which occurs in cardiac myocytes from failing hearts, impairs mitochondrial Ca 2ϩ uptake and the bioenergetic feedback response. This mechanism could contribute to energy starvation of failing hearts. (Circulation. 2010;122:2273-2280.) The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.110.968057/DC1.
doi:10.1161/circulationaha.110.968057 pmid:21098439 fatcat:4dgxemnrongjxor7ww73xg3uuy