Prolonged Hypoxia Decreases Nuclear Pyruvate Dehydrogenase Complex and Regulates the Gene Expression

Cells require proper regulation of energy metabolism to maintain cellular homeostasis. Pyruvate dehydrogenase (PDH) is a metabolic enzyme that converts pyruvate into acetyl-CoA, connecting glycolysis to the TCA cycle, thus regulating cellular energy metabolism. PDH is involved in multiple cellular processes, such as glucose metabolism, fatty acid synthesis, and protein acetylation, all of which are mediated by acetyl-CoA. We previously demonstrated that PDH-E1β is downregulated in prolonged hypoxia and inhibits PDH activity, which serves as machinery to securely inhibit PDH activity together with PDH-E1α phosphorylation. PDH has been identified to localize to the nucleus in addition to mitochondria, but its precise regulatory mechanisms in the nucleus remain elusive. In the present study, we characterized nuclear PDH during prolonged hypoxia. Nuclear PDH complex was downregulated under hypoxic conditions, and PDH activity was reduced. Depletion of HIF-1α partly recovered nuclear levels of the PDH complex. Furthermore, decreased nuclear PDH activity resulted in reduced histone H3 acetylation, altering the gene expression profile of cells exposed to prolonged hypoxia. Taken together, these findings indicate that nuclear PDH complex is downregulated under prolonged hypoxic conditions and controls gene expression.