On the Mechanism of Inhibition of Fatty Acid Oxidation by 4-Pentenoic Acid in Rat Liver Mitochondria

Abstract

Abstract The effects of 4-pentenoic acid on substrate oxidations and on the distribution of coenzyme A and its derivatives were studied in isolated rat liver mitochondria. CoA-linked substrate, long and short chain fatty acid, pyruvate, and α-ketoglutarate oxidations were inhibited 60 to 80% by 0.1 mm 4-pentenoic acid. The failure of 4-pentenoic acid to inhibit fatty acid oxidation in uncoupled mitochondria indicated that it was necessary for 4-pentenoic acid to be activated to its CoA ester to become inhibitory. Oxidation-reduction changes of mitochondrial pyridine nucleotides and flavoproteins following 4-pentenoic acid addition showed that the inhibitor itself could undergo β oxidation. The addition of 4-pentenoic acid caused CoA and acetyl-CoA levels to decrease while acid-soluble and acid-insoluble acyl-CoA levels increased. The observed changes were interpreted as indicating that free CoA was being incorporated into a product of 4-pentenoic acid metabolism, and inhibition of fatty acid oxidation was caused by CoA depletion. These conclusions were supported by the reversal of 4-pentenoic acid inhibition of palmitylcarnitine oxidation in ultrasonically disrupted mitochondria by the addition of CoA, while oxidation of palmityl-CoA was not inhibited in this preparation.