PDHA1 encodes the alpha-1 subunit of pyruvate dehydrogenase (PDH) E1, a critical mitochondrial enzyme that catalyzes pyruvate conversion to acetyl-CoA and CO2 12. As part of the heteromeric E1 complex with PDHB, PDHA1 performs thiamine pyrophosphate-dependent decarboxylation and reductive acetylation of lipoyl groups, linking glycolysis to the tricarboxylic acid cycle 23. PDHA1 activity is regulated through post-translational modifications; hyperacetylation impairs enzymatic function, increasing lactate production and promoting sepsis-induced kidney injury 4, while succinylation alters metabolic flux and suppresses macrophage antigen presentation in cholangiocarcinoma 5. Additionally, Pim2-mediated phosphorylation of PDHA1 enhances glycolytic reprogramming in inflammatory macrophages 6. PDHA1 mutations cause severe disease phenotypes: Leigh syndrome with the highest mortality rates among mitochondrial disorders 7, episodic ataxia presentations 8, and congenital metabolic myopathies 9. TCA cycle inhibition through PDHA1 suppression enhances anti-PD-1 immunotherapy efficacy in melanoma 10. These findings establish PDHA1 as a central metabolic hub whose dysfunction contributes to neurological, metabolic, and immune-related pathologies.