Human 2-Oxoglutarate Dehydrogenase and 2-Oxoadipate Dehydrogenase Both Generate Superoxide/H 2 O 2 in a Side Reaction and Each Could Contribute to Oxidative Stress in Mitochondria

According to recent findings, the human 2-oxoglutarate dehydrogenase complex (hOGDHc) could be an important source of the reactive oxygen species in the mitochondria and could contribute to mitochondrial abnormalities associated with multiple neurodegenerative diseases, including Alzheimer’s disease, Huntington disease, and Parkinson’s disease. The human 2-oxoadipate dehydrogenase (hE1a) is a novel protein, which is encoded by the DHTKD1 gene. Both missence and nonsense mutations were identified in the DHTKD1 that lead to alpha-aminoadipic and alpha-oxoadipic aciduria, a metabolic disorder with a wide variety of the neurological abnormalities, and Charcot-Marie-Tooth disease type 2Q, an inherited neurological disorder affecting the peripheral nervous system. Recently, the rare pathogenic mutations in DHTKD1 and an increased H 2 O 2 production were linked to the genetic ethiology of Eosinophilic Esophagitis (EoE), a chronic allergic inflammatory esophageal disorder. In view of the importance of hOGDHc in the tricarboxylic acid cycle (TCA cycle) and hE1a on the l -lysine, l -hydroxylysine and l -tryptophan degradation pathway in mitochondria, and to enhance our current understanding of the mechanism of superoxide/H 2 O 2 generation by hOGDHc, and by human 2-oxoadipate dehydrogenase complex (hOADHc), this review focuses on several novel and unanticipated recent findings in vitro that emerged from the Jordan group’s research. Most significantly, the hE1o and hE1a now join the hE3 as being able to generate the superoxide/H 2 O 2 in mitochondria.