We present an integrated thermokinetic model describing control of cardiac mitochondrial
bioenergetics. The model describes the tricarboxylic acid (TCA) cycle, oxidative phosphorylation,
and mitochondrial Ca(2+) handling. The kinetic component of the model includes effectors
of the TCA cycle enzymes regulating production of NADH and FADH(2), which in turn
are used by the electron transport chain to establish a proton motive force (Delta
mu(H)), driving the F(1)F(0)-ATPase. In addition, mitochondrial matrix Ca(2+), determined
by Ca(2+) uniporter and Na(+)/Ca(2+) exchanger activities, regulates activity of the
TCA cycle enzymes isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase.
The model is described by twelve ordinary differential equations for the time rate
of change of mitochondrial membrane potential (Delta Psi(m)), and matrix concentrations
of Ca(2+), NADH, ADP, and TCA cycle intermediates. The model is used to predict the
response of mitochondria to changes in substrate delivery, metabolic inhibition, the
rate of adenine nucleotide exchange, and Ca(2+). The model is able to reproduce, qualitatively
and semiquantitatively, experimental data concerning mitochondrial bioenergetics,
Ca(2+) dynamics, and respiratory control. Significant increases in oxygen consumption
(V(O(2))), proton efflux, NADH, and ATP synthesis, in response to an increase in cytoplasmic
Ca(2+), are obtained when the Ca(2+)-sensitive dehydrogenases are the main rate-controlling
steps of respiratory flux. These responses diminished when control is shifted downstream
(e.g., the respiratory chain or adenine nucleotide translocator). The time-dependent
behavior of the model, under conditions simulating an increase in workload, closely
reproduces experimentally observed mitochondrial NADH dynamics in heart trabeculae
subjected to changes in pacing frequency. The steady-state and time-dependent behavior
of the model support the hypothesis that mitochondrial matrix Ca(2+) plays an important
role in matching energy supply with demand in cardiac myocytes.