PERMEABILITY REGULATION IN MITOCONDRIA

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This project investigates the inner membrane permeability transition in liver and heart mitochondria. Our long-range goals are: to determine the nature of the structure which facilitates solute movements across the inner membrane following the transition (the permeability defect); to determine how the transition is regulated metabolically; and to identify the roles that the transition plays in physiological and pathological states. The proposed studies revolve around our recent discovery that the immunosuppressive cyclic peptide, cyclosporin A, is a highly potent and universal inhibitor of the transition. This is the first high activity inhibitor of the phenomenon to be identified. Its actions on mitochondria have led to the working hypothesis that the transition can occur by two interactive mechanisms which are the opening of a regulated proteinaceous pore within the inner membrane, and the creation of permeability defects in the membrane lipid phase subsequent to the action of phospholipase A2. For the support period requested, we have the following specific aims: 1) to characterize and isolate the cyclosporin A binding site and to reconstitute it into phospholipid vesicles if it is the pore; 2) to identify the full spectrum of stimulated phospholipid metabolism which accompanies the transition and to ascertain if and how phospholipid degradation is related to permeability control; 3) to characterize the putative cyclosporin-sensitive pore at the mitochondrial level with respect to regulation by known activators and inhibitors of the transition and with respect to energy utilization by mitochondria; and 4) to test working hypotheses on potential physiological roles of the transition and its involvement in mechanisms of cell injury initiated by oxidative stress.