Relationship of the ATP/ADP ratio to the site of octanoate activation

Following preincubation of isolated rat liver mitochondria in the absence of substrate, the carnitine-independent oxidation of octanoate or butyrate was markedly depressed when compared to rates observed with nonpreincubated mitochondria. Carnitine addition prevented the inhibition of octanoate oxidation but not that of butyrate. 2-Tetradecylglycidic acid or Zwittergent 3-08 (Z3-08) completely blocked the effect of carnitine. Replacement of ATP in the nonpreincubated incubation system with ADP mimicked the effect of preincubation by inhibiting octanoate and butyrate oxidation. This inhibition of octanoate oxidation was also prevented by carnitine addition. There was a direct and causal relationship between the ATP/ADP ratio of the total adenine nucleotide pool and the rate of carnitine-independent octanoate oxidation in mitochondria. The depression of octanoate oxidation was associated with a decrease in the intramitochondrial AMP content and intra- and extramitochondrial ATP/ADP ratios. In a cellular system, incubating isolated hepatocytes with fructose or glycerol to lower the ATP/ADP ratio resulted in greater inhibition of octanoate oxidation by 2-tetradecylglycidic acid. The data suggest that the ATP/ADP ratio may have a role in determining the site of octanoate activation and subsequent route of oxidation.