TRANSPORT IN CHOLESTEROL-RICH TUMOR MITOCHONDRIA

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The relationship between the well-documented enrichment of tumor mitochondrial membranes with cholesterol in vivo and the kinetics of citrate exchange transport across the mitochondrial membranes of Morris hepatomas continue to be the principal objectives of these studies. Our previously proposed "truncated" Krebs cycle in cholesterol-rich tumor mitochondria appears to have obtained further experimental support. Moreover, our recent studies during this grant period have indicated that there is a direct correlation between the extent of mitochondrial membrane enrichment with cholesterol and the extent of preferential citrate export from the mitochondrial matrix to the cytosolic compartment. Thus, we have shown that exogenous enrichment with cholesterol of normal liver mitochondria via our "solid-state" molecule transfer method yields patterns of carbon flux from pyruvate through mitochondrially exported citrate that mimics those obtained with tumor mitochondria. Among our specific objectives for the year 1984 to 1985 is the assessment of whether 14C-pyruvate-generated citrate carbons are preferentially incorporated into newly synthesized cholesterol, or whether they appear predominantly as 14CO2, when incubations of surviving tissue slices obtained from Morris hepatoma 3924A are compared with those from normal liver. Preferential incorporation of pyruvate-derived carbons into newly generated cholesterol in tumor tissue would strongly support our proposed altered pattern of metabolism in tumors, including a shift in the source of bioenergetic fuel used by tumors relative to normal tissue. (E)