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The Effects of Cycloheximide on Energy Transfer in Rat and Guinea Pig Liver Mitochondria

From the ¹ From the Fels Research Institute and Departments of Biochemistry and Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Cycloheximide was found to inhibit rat and guinea pig liver mitochondrial respiration in State 3 and after uncoupling by carbonyl cyanide p - trifluoromethoxyphenylhydrazone, although no effect was observed during State 4 respiration. This inhibition was dependent upon the nature of the mitochondrial substrate since oxygen consumption, pyridine nucleotide oxidation, and ADP phosphorylation were inhibited with all NAD⁺-linked substrates tested whereas no significant effects were noted with flavin-linked substrates such as succinate. Reversed electron transport was estimated directly by pyridine nucleotide fluorescence or by the formation of -hydroxybutyrate following succinate addition. In both instances, cycloheximide caused a significant inhibition. No direct effect of this inhibitor on a variety of purified NAD⁺-dependent dehydrogenases could be shown. Unlike rotenone, but similar to Amytal, cycloheximide significantly depressed the activity of the uncoupler-stimulated adenosine triphosphatase in isolated mitochondria. Taken together, these findings indicate that cycloheximide inhibits the mechanism of energy transfer specifically at Site I, but not at Sites II and III of the electron transport chain. Similar results were obtained with the isolated mitochondria of both rat and guinea pig liver. However, cycloheximide, in guinea pig liver mitochondria, produced a profound inhibition of P-enolpyruvate formation which was out of proportion to the observed inhibition of both substrate oxidation and ADP phosphorylation. The implications of this finding for the regulation of intramitochondrial guanine nucleotide balance are discussed.

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