A simulation study on the constancy of cardiac energy metabolites during workload transition

Abstract

The cardiac energy metabolites such as ATP, phosphocreatine, ADP and NADH are kept relatively constant over a wide range of cardiac workload, though the mechanisms are not yet clarified. One possible regulator of mitochondrial metabolism is Ca , because it activates several mitochondrial enzymes and transporters. Here we constructed a mathematical model of cardiac mitochondria, including oxidative phosphorylation, substrate metabolism and ion/substrate transporters, based on experimental data, and studied whether the Ca -dependent activation mechanisms play roles in metabolite constancy. Under the in vitro condition of isolated mitochondria, where malate and glutamate were used as mitochondrial substrates, the model well reproduced the Ca and inorganic phosphate (P ) dependences of oxygen consumption, NADH level and mitochondrial membrane potential. The Ca -dependent activations of the aspartate/glutamate carrier and the F F -ATPase, and the P -dependent activation of Complex III were key factors in reproducing the experimental data. When the mitochondrial model was implemented in a simple cardiac cell model, simulation of workload transition revealed that cytoplasmic Ca concentration ([Ca ] ) within the physiological range markedly increased NADH level. However, the addition of pyruvate or citrate attenuated the Ca dependence of NADH during the workload transition. Under the simulated in vivo condition where malate, glutamate, pyruvate, citrate and 2-oxoglutarate were used as mitochondrial substrates, the energy metabolites were more stable during the workload transition and NADH level was almost insensitive to [Ca ] . It was revealed that mitochondrial substrates have a significant influence on metabolite constancy during cardiac workload transition, and Ca has only a minor role under physiological conditions.

Control of Cardiac Mitochondrial Fuel Selection by Calcium

“…Numerous experimental and theoretical studies have supported the feedback hypothesis in the context of skeletal muscle (e.g., [10][11][12][13]). Similarly, in the heart the concentrations of ATP hydrolysis products increase with ATP demand in the myocardium in vivo [14][15][16][17][18][19][20][21][22], in agreement with the feedback hypothesis and providing additional evidence against the open-loop Ca 2+ hypothesis. Furthermore, our analyses suggest that a key difference between how oxidative ATP synthesis is controlled in skeletal versus cardiac muscle is that in the heart inorganic phosphate, and not ADP, controls the respiration rate [19][20][21][23][24][25].…”

Membrane current evoked by mitochondrial Na+–Ca2+ exchange in mouse heart

“…Mitochondrial Ca 2+ has pivotal roles in mitochondrial metabolism, apoptosis, and cytoplasmic Ca 2+ signaling [1][2][3][4][5]. Mitochondrial Ca 2+ influx is mainly mediated via mitochondrial Ca 2+ uniporter (MCU), and efflux via Na + -Ca 2+ exchanger (NCXm) and H + -Ca 2+ exchanger.…”

Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts

“…This mechanism is consistent with in vitro 42 , 43 and in vivo 1 , 7 , 44 data on cardiac energetics and is supported by theoretical investigations from several groups. 45–47 Based on this model, reduced mitochondrial capacity in the myocardium of TAC compared to control animals causes an increase in myocardial Pi because with reduced ATP synthesis capacity higher levels of ADP and Pi are needed to maintain ATP synthesis to match a given hydrolysis rate. Furthermore, at a given ATP hydrolysis rate, higher Pi levels are needed to compensate for the reduction in ADP caused by the reduced adenine nucleotide pool in myocardium from TAC animals.…”