PDHX (pyruvate dehydrogenase complex component X) encodes an essential structural protein that anchors the E3 subunit (dihydrolipoamide dehydrogenase) to the E2 core of the pyruvate dehydrogenase complex (PDC), a critical enzyme linking glycolysis to oxidative metabolism 1. PDHX is localized to the mitochondrial matrix where it facilitates pyruvate decarboxylation to acetyl-CoA through PDC assembly and function 2. At the molecular level, PDHX's E3-binding function is essential for PDC catalytic activity. Post-translational modifications regulate this function: acetylation of PDHX at Lys488 disrupts E2-E3 interactions, impairing PDC assembly and promoting aerobic glycolysis in hepatocellular carcinoma 3. Similarly, miR-27b-mediated suppression of PDHX in breast cancer alters pyruvate metabolism, reducing oxidative phosphorylation while promoting lactate production and cell proliferation 4. PDHX also undergoes S-depalmitoylation, which regulates its mitochondrial function 5. PDHX deficiency causes pyruvate dehydrogenase E3-binding protein deficiency, presenting as encephalopathy and severe lactic acidosis in neonates 16. PDHX mutations appear as secondary causes of episodic ataxia and cerebral palsy 72. Rapid diagnostics and dichloroacetate treatment show promise for managing PDHX-related mitochondrial disease 1.