System Analysis of Cardiac Energetics-Excitation-Contraction Coupling: Integration of Mitochondrial Respiration, Phosphotransfer Pathways, Metabolic Pacing, and Substrate Supply in the Heart

Because of high and changing energy demands and perfect structural, metabolic and functional organization of the cells (cardiomyocytes), heart muscle is a classical object of intense bioenergetic studies, and yet many unanswered questions remain. Recent progress in studies of cellular microcompartmentation, organized energetic units, and phosphotransfer networks, culminating in the concept of cardiac system bioenergetics, has significantly increased our understanding of how mitochondrial respiration and energy fluxes throughout cellular compartments are regulated, how energy is sensed, and how precise mechano-energetic coupling is maintained over a broad rage of functional activity. System analysis indicates that integration of cellular energetic systems with ion currents during action potential, Ca2th signaling, and changes in sarcomere length during muscle extension constitute the mechanisms of the basic Frank-Starling law of the heart. The changes in energy demand are transmitted to mitochondria by the networks of metabolic signaling via phosphotransfer pathways to regulate ATP production and thus maintain the energy homeostasis of the cell. Because of the metabolic sensors at the sarcolemma, coupled phosphotransfer reactions provide a highfidelity regulation of ion fluxes and excitation-contraction coupling. Here, we describe in quantitative terms the basic intracellular mechanisms of integration of energetics with calcium and magnesium signaling systems as a basis of metabolic pacing, synchronizing cellular electrical and mechanical activities with energy supply and substrate oxidation. Such analysis of cell energy metabolism as a whole functional unit at systemic level provides new insights about function of the most marvelous nature's created engine-the heart.