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.

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.

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.