PDHA1

The PDHA1 gene encodes Pyruvate Dehydrogenase E1 Subunit Alpha 1 (PDHE1α1), a core component of the mitochondrial pyruvate dehydrogenase complex (PDC). It catalyzes the rate-limiting oxidative decarboxylation of pyruvate to acetyl-CoA, bridging glycolysis and the tricarboxylic acid (TCA) cycle to regulate cellular energy metabolism. Its activity is tightly controlled by phosphorylation (inhibited) and dephosphorylation (activated) via PDK and PDP enzymes.
Mutations in PDHA1 cause PDC deficiency, leading to lactic acidosis, neurodevelopmental disorders, and neurodegeneration. Dysregulated PDHA1 is also linked to cancer’s Warburg effect. Dichloroacetate (DCA), a PDK inhibitor, restores PDHA1 function and has shown preclinical promise for metabolic diseases and certain cancers, though clinical efficacy requires further validation.