Abstract
The widely used mood stabilizer valproate (VPA) causes perturbation of energy metabolism, which is implicated in both the therapeutic mechanism of action of the drug as well as drug toxicity. To gain insight into these mechanisms, we determined the effects of VPA on energy metabolism in yeast. VPA treatment increased levels of glycolytic intermediates, increased expression of glycolysis genes, and increased ethanol production. Increased glycolysis was likely a response to perturbation of mitochondrial function, as reflected in decreased membrane potential and oxygen consumption. Interestingly, yeast, mouse liver, and isolated bovine cytochrome c oxidase were directly inhibited by the drug, while activities of other oxidative phosphorylation complexes (III and V) were not affected. These findings have implications for mechanisms of therapeutic action and toxicity.
Highlights
The widely used mood stabilizer valproate (VPA) causes perturbation of energy metabolism, which is implicated in both the therapeutic mechanism of action of the drug as well as drug toxicity
Consistent with an increase in glycolysis, we observed a significant increase in ethanol production after 5 h and to a greater extent after 10 h (Fig. 1)
We show that clinically relevant concentrations of VPA increase carbon accumulation through glycolysis and decrease mitochondrial bioenergetics
Summary
The widely used mood stabilizer valproate (VPA) causes perturbation of energy metabolism, which is implicated in both the therapeutic mechanism of action of the drug as well as drug toxicity. Yeast, mouse liver, and isolated bovine cytochrome c oxidase were directly inhibited by the drug, while activities of other oxidative phosphorylation complexes (III and V) were not affected These findings have implications for mechanisms of therapeutic action and toxicity. In addition to affecting ß-oxidation, VPA inhibits α-ketoglutarate dehydrogenase, a key enzyme of the tricarboxylic acid (TCA) c ycle[39,40] Inhibition of this enzyme is a proposed mechanism underlying decreased TCA cycle flux in the presence of V PA41. Other effects of VPA on mitochondrial energy metabolism include a decrease in pyruvate u ptake[44,45] and inhibition of mitochondrial oxidative p hosphorylation[44,46,47].
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