The objective of this study is to characterize structural and functional modifications of mitochondria and other organelles in liver cells, induced (via second messengers) by hormone-receptor interactions at the plasma membrane. The hypothesis will be studied that a glucagon-induced alteration in the physico-chemical properties of the mitochondrial membrane may account for the change in membrane related functional characteristics of the mitochondria. Mitochondrial membranes and reconstituted liposomes from control and glucagon-treated rats will be studied by 31P-NMR and by EPR analysis of spin labeled membranes. Susceptibility of the membranes to endogenous and exogenous phospholipase A2 will be investigated in relation to calcium retention characteristics. Reconstitution studies of nicotinamide nucleotide transhydrogenase and other membrane enzymes will be carried out to investigate the basis for the glucagon induced stimulation in intact mitochondria. The role of Ca++, cAMP and metabolites of polyphosphoinositides in the signal transfer to the mitochondria will be studied in intact and permeabilized hepatocytes as well as the effect of insulin on these parameters. These studies will give insight into the physiological implications of lipid-protein interactions in the mitochondrial membrane and in the use of membrane structure-function relationships for regulatory purpose. In addition, long-term adjustments to different nutritional and hormonal conditions, will be investigated, with special emphasis on diabetes.
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