In vitro studies on the oxidation of medium-chain dicarboxylic acids in rat liver

Abstract

The degradation of medium-chained dicarboxylic (DC) acids was investigated on purified mitochondria and peroxisomes. Intact organelles were incubated with dodecanedioic acid ( DC 12), sebacic acid (DC 10), suberic acid ( DC 8) and adipic acid ( DC 6), and the production of lower-chained DC-acids and of acetyl-CoA + acetyl-carnitine was monitored. It was shown, that intact peroxisomes could β-oxidize DC 12, DC 10 and DC 8 at least as far as DC 6, while intact mitochondria readily β-oxidized DC 12 and DC 10 as far as succinic acid. DC 8 and DC 6 were not oxidized by intact mitochondria when these two acids were presented externally to the intact organelle. When they were formed intramitochondrially from DC 12 and DC 10, both DC 8 and DC 6 were, however, to a great extent β-oxidized as far as succinic acid. The major reason for this difference between mitochondrial oxidation of externally and internally located DC 8 and DC 6 seems to be an inability to transport these two acids through the mitochondrial membrane. For DC 12 and dc 10, the mitochondrial transport systems, which were indicated to be identical to the systems used by the corresponding monocarboxylic acids, were found to be rate-limiting in the β-oxidation of these acids. A contributing factor to the undetectable β-oxidation of externally located DC 8 and DC 6 may also be, that the K m values of DC 8- CoA (460 ± 70 μmol/ l) and DC 6-CoA (980 ± 90 μmol/ l) towards the acyl-CoA dehydrogenases are very high. These results imply that very high concentrations of intermediates are created intramitochondrially during β-oxidation, concentrations which are probably only formed through formation of DC 8-CoA and DC 6-CoA from longer DC-acids and not by transport from outside the mitochondria. The data presented thus for the first time give evidence to a pathway for medium-chained monocarboxylic acids (especially lauric acid and decanoic acid) through cytosolic ω-oxidation followed by activation, transport over the mitochondrial membrane and β-oxidation to succinic acid.