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The role of mitochondrial changes in cancerogenesis is presently debated.Cancer cells are characterized by a high glycolytic phenotype with relative impairment of mitochondrial function (the Warburg effect).We have used a system of K-ras-transformed fibroblasts in comparison with immortalized normal counterparts to evaluate functional bioenergetic changes dependent upon ras oncogene activation.Ras-transformed fibroblasts have a decreased expression of several mitochondrial genes related to oxidative phosphorylation, including genes encoding for cytochrome oxidase and ATP synthase subunits.We have investigated bioenergetic parameters in digitonin-permeabilized cells grown to 60-80% confluence from normal NIH-3T3 mouse fibroblasts and K-ras-transformed fibroblasts derived from the same cell line.Using glutamate plus malate as substrates, respiration was strongly depressed in both State 3 and uncoupled conditions in the mitochondria from neoplastic cells, with concomitant strong decrease of the rate of ATP synthesis.The results were not affected by correcting for mitochondrial mass by citrate synthase assay.