1. Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae.
- Author
-
Salsaa M, Pereira B, Liu J, Yu W, Jadhav S, Hüttemann M, and Greenberg ML
- Subjects
- Animals, Glycolysis, Mice, Oxidative Phosphorylation drug effects, Oxygen Consumption, Prostaglandin-Endoperoxide Synthases metabolism, Energy Metabolism drug effects, Mitochondria drug effects, Mitochondria metabolism, Saccharomyces cerevisiae drug effects, Saccharomyces cerevisiae metabolism, Valproic Acid pharmacology
- 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.
- Published
- 2020
- Full Text
- View/download PDF