Control and regulation of mitochondrial energetics in an integrated model of cardiomyocyte function

Understanding the regulation and control of complex networks of reactions requires analytical tools that take into account the interactions between individual network components controlling global network function. Here, we apply a generalized matrix method of control analysis to calculate flux and concentration control coefficients, as well as response coefficients, in an integrated model of excitation-contraction (EC) coupling and mitochondrial energetics (ECME model) in the cardiac ventricular myocyte. Control and regulation of oxygen consumption (V_O2) was first assessed in a mitochondrion model, and then in the integrated cardiac myocyte model under resting and working conditions. The results demonstrate that in the ECME model, control of respiration is distributed among cytoplasmic ATPases and mitochondrial processes. The magnitude of control by cytoplasmic ATPases increases under working conditions. The model prediction that the respiratory chain exerts strong positive control on V_O2 (control coefficient 0.89) was corroborated experimentally in cardiac trabeculae utilizing the inhibitor titration method. In the model, mitochondrial respiration displayed the highest response coefficients with respect to the concentration of cytoplasmic ATP. This was due to the high elasticity of ANT flux toward ATP in the cytoplasm. The analysis reveals the complex interdependence of sarcolemmal, cytoplasmic, and mitochondrial processes that contribute to the control of energy supply and demand in the heart. Moreover, by visualizing the structure of control of the metabolic network of the myocyte, we provide support for the emerging concept of control by diffuse loops, in which action on the network (e.g., by a pharmacological agent) may bring about changes in processes without obvious direct mechanistic links between them.