Mitochondrial Calcium Signaling and Energy Metabolism

Abstract

A computational model of energy metabolism in the mammalian ventricular myocyte is developed to study the effect of cytosolic calcium (Ca(2+)) transients on adenosine triphosphate (ATP) production. The model couples the Jafri-Dudycha model for tricarboxylic acid cycle regulation to a modified version of the Magnus-Keizer model for the mitochondria. The fluxes associated with Ca(2+) uptake and efflux (i.e., the Ca(2+) uniporter and Na(+)-Ca(2+) exchanger) and the F(1)F(0)-ATPase were modified to better model heart mitochondria. Simulations were performed at steady state and with Ca(2+) transients at various pacing frequencies generated by the Rice-Jafri-Winslow model for the guinea pig ventricular myocyte. The effects of the Ca(2+) transients for mitochondria both adjacent to the dyadic space and in the bulk myoplasm were studied. The model shows that Ca(2+) activation of both the tricarboxylic acid cycle and the F(1)F(0)-ATPase are necessary to produce increases in ATP production. The model also shows that in mitochondria located near the subspace, the large Ca(2+) transients can depolarize the mitochondrial membrane potential sufficiently to cause a transient decline in ATP production. However, this transient is of short duration, minimizing its impact on overall ATP production.