Pyruvate dehydrogenase complex and other mitochondrial alpha-keto acid dehydrogenases (OADHCs)

The pyruvate dehydrogenase complex (PDC) and other mitochondrial alpha-keto acid dehydrogenases, including alpha-ketoglutarate dehydrogenase (KGDH) and branched-chain alpha-keto acid dehydrogenase (BCKDH), are essential multienzyme complexes that regulate key checkpoints in mitochondrial metabolism [StatPearls, PMID: 30020664]. These complexes catalyze the oxidative decarboxylation of alpha-keto acids, facilitating the conversion of metabolic intermediates into acetyl-CoA or succinyl-CoA to fuel the citric acid cycle [UniProt, P08559]. Structurally, they are composed of multiple copies of three core enzymes (E1, E2, and E3) and require cofactors such as thiamine pyrophosphate, lipoic acid, and NAD+ [Wikipedia, 2-oxoacid dehydrogenase complex]. In many cancers, these enzymes are dysregulated to support the Warburg effect, making them attractive targets for metabolic inhibitors like devimistat (CPI-613), which mimics the lipoate cofactor to disrupt mitochondrial respiration [PubChem, CID 11510144]. Additionally, genetic deficiencies in these complexes lead to severe metabolic disorders like maple syrup urine disease and congenital lactic acidosis [NIH, Genetic and Rare Diseases Information Center]. Therapeutic intervention often focuses on either restoring activity through cofactor supplementation or selectively inhibiting them to starve energy-hungry tumor cells [PubMed, PMID: 24755155].

Other names

2-oxoacid dehydrogenase complexesMitochondrial alpha-keto acid dehydrogenase complexes2-oxo acid dehydrogenase multienzyme complexesalpha-KADH complexes

Inhibition of mitochondrial energy metabolism through the inactivation of the E2 subunit of the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes; or activation of the complex via inhibition of regulatory kinases.