Computer-aided analysis of biochemical mechanisms that increase metabolite and proton stability in the heart during severe hypoxia and generate post-ischemic PCr overshoot

Abstract

During severe hypoxia in the heart, impaired supply of ATP by oxidative phosphorylation could lead to a great drop in ATP turnover and heart work. Anaerobic glycolysis enables unchanged ATP turnover to be maintained, but leads to huge changes in metabolite (PCr, ATP, ADP, Pi) concentrations and to cytosol acidification. A computer model of heart energetics developed previously is used to analyze semi-quantitatively the effect of different processes/mechanisms that can partly counteract these effects. Down-regulation of ATP usage compromises cardiac output, but reduces changes in cytosolic pH and metabolite concentrations. AMP decomposition delays cytosol acidification but reduces metabolite homeostasis (concentration stability). An increase in the parallel activation of oxidative phosphorylation (OXPHOS) (a hypothetical mechanism involving direct activation of all OXPHOS complexes by a cytosolic factor, postulated to take place also during work increase) reduces cytosol acidification and elevates metabolite homeostasis. All these mechanisms can generate the post-ischemic PCr overshoot. © The Physiological Society of Japan and Springer 2011.