Pyruvate dehydrogenase deficiency hijacks B12 to sustain energy production

The pyruvate dehydrogenase complex (PDC) serves as the crucial gate between cytosolic and mitochondrial metabolism1. In humans, PDC deficiency (PDCD) leads to a severe mitochondrial disorder without effective treatment2,3,4. Beyond its known enzymatic defect, the broader metabolic consequences of PDCD remain unclear. Using cross-species approaches spanning Caenorhabditis elegans, mouse primary hepatocytes, human cell lines, and patient blood samples, we reveal a conserved and obligatory metabolic trade-off in PDCD: functional depletion of vitamin B12. This loss is driven by compensatory rewiring via an MDT-15/MED15-NHR-68/HNF4 pathway, diverting carbon flux from B12-dependent propionate metabolism to sustain acetyl-CoA synthesis and mitochondrial function. Thus, PDCD triggers an acquired B12 deficiency as a survival strategy. Therapeutically, this vulnerability is targetable, as acetate supplementation restores acetyl-CoA levels and rescues B12 function. Our work reveals a fundamental adaptive principle where a vital vitamin-dependent pathway is sacrificed to maintain core energy production, unveiling novel therapeutic avenues.