Mitochondrial Calcium Signaling and Energy Metabolism

摘要

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_1F_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_1F_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.