1. DL-8-Methyldihydrolipoate was shown to be a potent inhibitor of mitochondrial oxidative phosphorylation and ATP-driven energy-linked reactions. 2. ADP-stimulated respiration utilizing pyruvate + malate and succinate in both ox heart and rat liver mitochondria is inhibited; oxidative phosphorylation using pyruvate + malate, succinate and ascorbate + NNN'N'-tetramethyl-p-phenylenediamine as substrates is also inhibited; uncoupler-stimulated respiration is unaffected regardless of the substrate used. 3. Mitochondrial oligomycin-sensitive adenosine triphosphatase is inhibited in both the membrane-bound form and the purified detergent-dispersed preparation. 4. ATP-driven transhydrogenase and the ATP-driven energy-linked reduction of NAD+ by succinate in ox heart submitochondrial particles are inhibited, whereas the respiratory-chain-driven transhydrogenase is unaffected. 5. DL-8-Methyl-lipoate has no immediate effect on the above reactions, demonstrating the requirement for the reduced form for inhibition. 6. The inhibitory properties of DL-8-methyldihydrolipoate are analogous to those of oligomycin and provide further evidence of a role for lipoic acid in oxidative phosphorylation.
Studies of the mode of action of dibutylchloromethyltin chloride have shown that it reacts with a lipoic acid moiety present in high concentrations in the mitochondrial inner membrane and which is also present in stoicheiometric amounts in purified ATP synthase preparations (3-611101 of lipoic acid/mol of ATP synthase) (Griffiths, 1976a,b). This component has not been characterized, but has the properties of an ester of lipoic acid with an unidentified lipid component. The presence of large amounts of lipoic acid residues that are distinct from the protein-bound lipoic acid moieties of thepyruvateand a-oxoglutarate dehydrogenase complexes, together with evidence that the inhibitors Vol. 5
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