Cellular energetics in the preconditioned state - Protective role for phosphotransfer reactions captured by O-18-assisted P-31 NMR

Cell survival is critically dependent on the preservation of cellular bioen ergetics. However, the metabolic mechanisms that confer resistance to injur y are poorly understood. Phosphotransfer reactions integrate ATP-consuming with ATP-producing processes and could thereby contribute to the generation of a protective phenotype. Here, we used ischemic preconditioning to induc e a stress-tolerant state and O-18-assisted P-31 nuclear magnetic resonance spectroscopy to capture intracellular phosphotransfer dynamics. Preconditi oning of isolated perfused hearts triggered a redistribution in phosphotran sfer flux with significant increase in creatine kinase and glycolytic rates . High energy phosphoryl fluxes through creatine kinase, adenylate kinase, and glycolysis in preconditioned hearts correlated tightly with post-ischem ic functional recovery. This was associated with enhanced metabolite exchan ge between subcellular compartments, manifested by augmented transfer of in organic phosphate from cellular ATPases to mitochondrial ATP synthase. Prec onditioning-induced energetic remodeling protected cellular ATP synthesis a nd ATP consumption, improving contractile performance following ischemia-re perfusion insult. Thus, the plasticity of phosphotransfer networks contribu tes to the effective functioning of the cellular energetic system, providin g a mechanism for increased tolerance toward injury.