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Energy Metabolism in Rat Brain: Inhibition of Pyruvate Decarboxylation by 3‐Hydroxybutyrate in Neonatal Mitochondria

Abstract: The effect of 3‐hydroxybutyrate on pyruvate decarboxylation by neonatal rat brain mitochondria and synaptosomes was investigated. The rate of [1 ‐14C]pyruvate decarboxylation (1 mm final concentration) by brain synaptosomes derived from 8‐day‐old rats was inhibited by 10% in the presence of 2 mm‐d,l‐3‐hydroxybutyrate and by more than 20% in the presence of 20 mm‐d,l‐3‐hydroxybutyrate. The presence of 2 mm‐l,d‐3‐hydroxybutyrate did not affect the rate of [1‐14T]pyruvate decarboxylation (1 mm final concentration) by brain mitochondria; however, at a concentration of 20 mm‐d,l‐3‐hydroxybutyrate, a marked inhibition was seen in preparations from both 8‐day‐old (35% inhibition) and 21‐day‐old (24% inhibition) but not in those from adult rats. Although the presence of 100 mm‐K+ in the incubation medium stimulated the rate of pyruvate decarboxylation by approximately 50% compared with the rate in the presence of 1 mm‐K+, the presence of 20 mm‐d,l‐3‐hydroxybutyrate still caused a marked inhibition in both media (1 and 100 mm‐K+). The presence of 20 mm‐d,l‐3‐hydroxybutyrate during the incubation caused an approximately 20% decrease in the level of the active form of the pyruvate dehydrogenase complex in brain mitochondria from 8‐day‐old rats. The concentrations of ATP, ADP, NAD+, NADH, acetyl CoA, and CoA were measured in brain mitochondria from 8‐day‐old rats incubated in the presence of 1 mm‐pyruvate alone or 1 mm‐pyruvate plus 20 mm‐d,l‐3‐hydroxybutyrate. Neither the ATP/ADP nor the NADH/NAD+ ratio showed significant changes. The acetyl CoA/CoA ratio was significantly increased by more than twofold in the presence of 3‐hydroxybutyrate. The possible mechanisms and physiological significance of 3‐hydroxybutyrate inhibition of pyruvate decarboxylation in neonatal rat brain mitochondria are discussed.