Abstract
The regulation of cardiac cellular bioenergetics is critical for maintaining normal cell function, yet the nature of this regulation is not fully understood. Different mechanisms have been proposed to explain how mitochondrial ATP production is regulated to match changing cellular energy demand while metabolite concentrations are maintained. We have developed an integrated mathematical model of cardiac cellular bioenergetics, electrophysiology, and mechanics to test whether stimulation of the dehydrogenase flux by Ca2+ or Pi, or stimulation of complex III by Pi can increase the rate of mitochondrial ATP production above that determined by substrate availability (ADP and Pi). Using the model, we show that, under physiological conditions the rate of mitochondrial ATP production can match varying demand through substrate availability alone; that ATP production rate is not limited by the supply of reducing equivalents in the form of NADH, as a result of Ca2+ or Pi activation of the dehydrogenases; and that ATP production rate is sensitive to feedback activation of complex III by Pi. We then investigate the mechanistic implications on cytosolic ion homeostasis and force production by simulating the concentrations of cytosolic Ca2+, Na+ and K+, and activity of the key ATPases, SERCA pump, Na+/K+ pump and actin-myosin ATPase, in response to increasing cellular energy demand. We find that feedback regulation of mitochondrial complex III by Pi improves the coupling between energy demand and mitochondrial ATP production and stabilizes cytosolic ADP and Pi concentrations. This subsequently leads to stabilized cytosolic ionic concentrations and consequentially reduced energetic cost from cellular ATPases.
Highlights
Cardiac myocytes utilize the free energy of ATP hydrolysis (DGATP) to drive key cellular processes responsible for force development and cellular ion homeostasis
The concentrations of these metabolites are variables in the model, and these steady-state values are determined by the dynamic feedback between energy demand and energy supply
To validate the ATPase rates predicted by the model, we compare the output of the model to data from Schramm et al (1994) who measured the active rate of heat production in guinea pig ventricular myocytes at 37°C in order to determine the relative contributions of the three main ATPases in the cell
Summary
Cardiac myocytes utilize the free energy of ATP hydrolysis (DGATP) to drive key cellular processes responsible for force development and cellular ion homeostasis. When transitioning from a low to a high workload, the myocyte can match the rate of mitochondrial ATP production to a several-fold increase in ATP utilization with little or no observed changes in the concentrations of metabolite intermediates (Balaban et al 1986). This regulation is both remarkable and of paramount importance to the normal functioning of the heart, and is a central question of cardiac physiology that is yet to be fully understood
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