Mammalian 2-Oxo Acid Dehydrogenase Complexes in Metabolic Regulation and Signaling

2-Oxo acid dehydrogenase complexes include four members that oxidatively decarboxylate pyruvate, 2-oxoglutarate, 2-oxoadipate, and branched-chain 2-oxo acids. The complexes produce CO₂, acylated coenzyme A, and NADH through consecutive action of three enzymes with their coenzymes: 2-oxo acid dehydrogenase with thiamine diphosphate, dihydrolipoyllysine-residue acyltransferase with the lipoyllysine prosthetic group, and dihydrolipoyl dehydrogenase with FAD. Some of the complexes include additional regulatory proteins. Producing energy in the form of NADH and acyl-CoAs, which are feedback inhibitors, the complexes mediate the Ca2+ activation of mitochondrial function, couple metabolism of glucose and amino acids, are essential for biosynthesis of the signaling molecules acetylcholine and glutamate, regulate metabolism through posttranslational acylations, including histone acylations, and sense the metabolic imbalance as nonoptimal ratios of their substrates and products. The complexes signal the imbalance by the generation of reactive species: O₂•-, thiyl radicals, thiamine-dependent carbon radicals, and/or peracids, potentially involved in DNA damage and development of diseases.