The effect of eight branched-chain amino acid metabolites, four metabolites from the β-oxidation, and the unphysiologic acid 4-pentenoic acid on the oxygen consumption rate of liver mitochondria oxidizing pyruvate, 2-oxo-glutarate, and L-palmitoylcarnitine has been investigated. The 12 metabolites are: propionic, isobu-tyric, 2-Me-butyric, isovaleric, acrylic, Me-acrylic, tiglic, Me-crotonic, butyric, hexanoic, crotonic, and 2-hexenoic acids. The oxidation rate of pyruvate was strongly inhibited by propionic, 4-pentenoic, and isovaleric acids at 0.1, 0.1, and 1.0 mM, respectively. With 2-oxo-glutarate as substrate, the oxygen consumption rate was strongly inhibited at 0.1 mM of propionic, 4-pentenoic, and isovaleric acids. The L-palmitoyl-carnitine oxidation rate was very strongly inhibited by 0.1 mM 4-pentenoic acid, whereas butyric and hexanoic acids exerted a moderate inhibition at 0.1 mM. Propionic acid inhibited L-palmitoylcarnitine oxidation slightly at 1.0 mM. It is argued that propionyl-CoA and isovaleryl-CoA inhibit pyruvate and 2-oxo-glutarate dehydrogenases directly, and the significance of the results for ketotic episodes in organic acidurias is discussed.SpeculationThe significant inhibition of energy metabolism by propionic and isovaleric acids compared to the other monocarboxylic acids suggests a direct inhibition of pyruvate and 2-oxo-glutarate dehydrogenases in mitochondria incubated with propionic or isovaleric acids. It may be speculated that the inhibition of the pyruvate metabolism in the intact cell, may cause an accumulation of pyruvate and lactate, and that the inhibition of the 2-oxo-glutarate oxidation may be ketogenetic by lowering the cellular oxaloacetate concentration. The excessive excretion and accumulation of propionic and/or isovaleric acid in acute episodes and the terminal phases of some organic acidurias is consistent with the hypothesis that these acids contribute to the pathophysiology of the acute disease states.