Mitochondrial 2-oxoacid dehydrogenase complexes (OADHCs)

Mitochondrial 2-oxoacid dehydrogenase complexes (OADHCs) are a family of high-molecular-weight multi-enzyme assemblies located within the mitochondrial matrix that catalyze the oxidative decarboxylation of alpha-ketoacids [1]. This family includes the pyruvate dehydrogenase complex (PDC), the 2-oxoglutarate dehydrogenase complex (OGDC), and the branched-chain 2-oxoacid dehydrogenase complex (BCOADC) [2]. These complexes are central to cellular energy metabolism, linking glycolysis and amino acid catabolism to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation [1, 2]. Structurally, they consist of multiple copies of three core enzymes (E1, E2, and E3) and utilize several cofactors, including thiamine pyrophosphate, lipoic acid, and NAD+ [2]. Dysregulation or deficiency of these complexes is associated with various pathologies, including metabolic disorders like maple syrup urine disease, primary biliary cholangitis (where they serve as major autoantigens), and cancer [5]. Therapeutic strategies often involve modulating these complexes to alter metabolic flux, such as using dichloroacetate to activate PDC in cancer or lactic acidosis, or using inhibitors like devimistat to disrupt mitochondrial metabolism in tumor cells [3, 4].

Other names

Alpha-ketoacid dehydrogenase complexes2-oxoacid dehydrogenase complexesMitochondrial alpha-ketoacid dehydrogenase complexes

Modulation of complex activity through either the inhibition of regulatory kinases (e.g., pyruvate dehydrogenase kinase) to increase metabolic flux or the direct inhibition of lipoate-dependent E2 subunits to disrupt mitochondrial energy production in cancer cells.