Evidence for the important physiological role of the creatine kinase (CK)- phosphocreatine (PCr) system in energy homeostasis in sarcomeric muscle, brain, and other organs of high and fluctuating energy requirements is presented in the context of defined subcellular compartments of CK isoenzymes with processes of energy production, i.e., glycolysis and mitochondrial oxidative phosphorylation, and those of energy utilization, i.e., ATPases, ATP-gated ion channels, and ATP-dependent signaling events. The concepts of functional coupling and metabolite channeling are discussed, and the CK subcompartments that have been characterized in great detail are described. Mitochondrial CK (MtCK) plays a central role (1) in high-energy phosphoryl transfer and channeling, (2) in metabolic feedback regulation of mitochondrial respiration in vivo, (3) in stabilizing the contact sites of inner and outer mitochondrial membranes, (4) in delaying and preventing mitochondrial permeability pore opening, an early event in apoptosis, and (5) in preventing, by efficient ADP recycling inside mitochondria and by optimal coupling of respiration with ATP synthesis, excessive free oxygen radical (ROS) formation. Additional new and exciting findings indicate that octameric MtCK, a highly symmetrical cube-like molecule that is able to cross-link two membranes, is also involved in lipid transfer between mitochondrial membranes and in clustering of cardiolipin (CL) and the formation of membrane patches. Because of the high reactivity of the active-site cysteine of CK isoenzymes, this enzyme is highly susceptible to oxidation that leads to inactivation. Oxidation of other residues at the dimer-dimer interface of MtCK induces dimerization of the MtCK octamer, the functional entity in the mitochondrial intermembrane space, and dissociation of MtCK from the mitochondrial membranes. (PDF) The Phosphocreatine Circuit: Molecular and Cellular Physiology of Creatine Kinases, Sensitivity to Free Radicals, and Enhancement by Creatine Supplementation. Available from: https://www.researchgate.net/publication/200159132_The_Phosphocreatine_Circuit_Molecular_and_Cellular_Physiology_of_Creatine_Kinases_Sensitivity_to_Free_Radicals_and_Enhancement_by_Creatine_Supplementation [accessed Dec 10 2018].