Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae.

Scientific Reports
Michael SalsaaMiriam L Greenberg

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.

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Citations

Aug 25, 2021·The Journal of Biological Chemistry·Michael SalsaaMiriam L Greenberg

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Methods Mentioned

BETA
fluorescence assay
flow cytometry
protein assay

Software Mentioned

FlowJo
Oxygraph

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