REGULATION OF ENERGY METABOLISM

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This project is designed to explore the regulation of energy provision by the process of oxidative phosphorylation and the changes which occur as a function of senescence and of disease-states. Particular emphasis is placed upon the control of substrate oxidation at the level of mitochondrial dehydrogenases. This year, we have asked the following questions. (1) What is the effect of the activation of 2-oxoglutarate dehydrongenase and pyruvate dehydrogenase by Ca ions on the proton electrochemical gradient maintained by rat heart mitochondria? We have approached this by measuring the mitochondrial membrane potential, the largest component of the proton gradient, using a potential-sensitive fluorescent dye, rhodamine 1,2,3 (2) What is the impact of senescence upon the activity of the mitochondrial isozyme of creatine kinase in rat heart? This enzyme forms part of the shuttle whereby ATP is made available at the myofibrils in an efficient manner, and its activity has been shown to be diminished in experimentally- induced hypertrophy. (3) Is mitochondrial energy transduction a limiting factor in the diminished contractile performance which is seen in a genetically-determined cardiomyopathy , viz. the BIO 14.6 strain of the Syrian hamster? If so, is there specifically a defect in mitochondrial pyruvate oxidation, associated with altered Ca ion homeostasis by mitochondria in this model? (4) What is the role of substrate-level phosphorylation by glycolysis in allowing tissue survival following cardiac ischemia? Specifically, what factors control the activity of glycogen phosphorylase in low-flow ischemia and upon subsequent reperfusion of the myocardium?