Fig. 1.

Oxidative metabolism and ROS production by 2-oxoglutarate (Ogdh). (A) Schematic illustration of the oxidation of carbon and oxidative phosphorylation in mitochondria. Electrons liberated from the oxidation of nutrients in the Krebs cycle are ferried through the respiratory chain the terminal electron acceptor di-oxygen (O₂). Electron movement is coupled to the formation of a membrane potential composed of electrochemical difference in protons which drives ATP production. Also depicted are the sites of ROS formation (red stars) in the nutrient oxidation and respiratory chain. Note that the red star in the Krebs cycle represents ROS formation by Ogdh and Pdh, respectively. Sites for ROS production in the electron transport chain include sn-glycero-3-phosphate dehydrogenase (G3pdh), Complexes I, II, and III. For simplicity, other ROS forming sites including electron-transferring flavoprotein-ubiquinone oxidoreductase (Etfqo), proline dehydrogenase (Prodh), dihydrolipoamide dehydrogenase (Dhodh), 2-oxoadipate dehydrogenase (Dhtkd1), and sulfide-quinone oxidoreductase (Sqo), were omitted. The reader is encouraged to consult these articles on the 12 sites of production in mitochondria [3], [20], [34], [35]. (B) Generation of ${\mathrm{O}}_2^{\bullet -}$/H₂O₂ by 2-oxoglutarate dehydrogenase Ogdh complex. The complex is composed of E₁ (2-oxoglutarate decarboxylase), E₂ (dihydrolipoamide succinyl transferase), and E₃ (dihydrolipoamide dehydrogenase) which couple 2-oxoglutarate oxidation to NADH formation. The enzyme complex contains multiple copies of each subunit indicated by a green outline. 2-Oxoglutarate is first oxidized by E₁ resulting in the liberation of CO₂ and the succinylation of thiamine pyrophosphate (TPP). The succinyl moiety is then transferred to a vicinal thiol on lipoamide in the E₂ subunit which then interacts with CoASH to yield succinyl-CoA and dihydrolipoamide. The dihydrolipoamide is re-oxidized by the E₃ subunit where the liberated electrons are transferred through FAD to reduce NAD⁺ forming NADH. Note that Ogdh contains two ROS generating sites depicted by red stars and can also be S-glutathionylated on all three subunits. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)