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

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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-D,L-3-hydroxybutyrate did not affect the rate of [1-14C]pyruvate decarboxylation (1 mM final concentration) by brain mitochondria; 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 2-fold 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.