Efflux of Adenine Nucleotides in Mitochondria from Rat Tumor Cells of Varying Growth Rates

The efflux of adenine nucleotides was studied in mitochondria isolated from normal rat liver, host livers, and the tumors from four Morris hepatoma lines of varying growth rates. [^Adenosine diphosphate (ADP) or [3H]adenosine triphosphate (ATP) was preloaded to the energized mitochondria, and the initial rates of exchange with unlabeled extramitochondrial nucleotides were measured with the carboxyatractyloside stop method. Results indicate that the Vmax values of ATP efflux in mitochondria from fast and intermediately growing tumors (hepatoma cell lines 7777, 7800, and 5123D) are significantly smaller than that of host or normal liver mitochondria, while in slow growing tumor (line 16) the is not different. On the other hand, for ADP efflux, the opposite (namely, higher in tumor than in host) is observed in the mitochondria of fast growing tumors. Preincubation with the divalent cation ionophore A23187 and calcium chelator ethyleneglycdbis(β -aminoethyl ether)-N,N '-tetraacetic acid increases the efflux of both ATP and ADP (to a lesser extent) in these tumor mitochondria, indicating that the extraordinarily high concentrations of calcium form complexes with adenine nucleotides (particularly ATP) and thus lower the effective concentrations of free nucleotides for translocation. Together with previously published results (R. L. Barbour and S. H. P. Chan, Cancer Res., 43: 1511-1517, 1983) on lower nucleotide uptake rates in these tumor mitochondria, we propose that the lower ATP efflux and higher ADP efflux rates may cause a futile cycle of ADP transport across the mitochondrial membrane which may contribute to high rates of aerobic glycolysis (by stimulating key glycolytic enzymes such as hexokinase and phosphofructokinase) observed in these fast and intermediately growing tumors.