Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

Abstract

Alpha-ketoglutarate dehydrogenase (alpha-KGDH) is a highly regulated enzyme, which could determine the metabolic flux through the Krebs cycle. It catalyses the conversion of alpha-ketoglutarate to succinyl-CoA and produces NADH directly providing electrons for the respiratory chain. alpha-KGDH is sensitive to reactive oxygen species (ROS) and inhibition of this enzyme could be critical in the metabolic deficiency induced by oxidative stress. Aconitase in the Krebs cycle is more vulnerable than alpha-KGDH to ROS but as long as alpha-KGDH is functional NADH generation in the Krebs cycle is maintained. NADH supply to the respiratory chain is limited only when alpha-KGDH is also inhibited by ROS. In addition being a key target, alpha-KGDH is able to generate ROS during its catalytic function, which is regulated by the NADH/NAD+ ratio. The pathological relevance of these two features of alpha-KGDH is discussed in this review, particularly in relation to neurodegeneration, as an impaired function of this enzyme has been found to be characteristic for several neurodegenerative diseases.

Figure 1

Metabolic flux in the Krebs cycle during oxidative stress when aconitase is completely inactivated. ^* Enzymes inhibited by H₂O₂. When aconitase, the most sensitive enzyme, is inhibited by 100% but α-KGDH is still functional in the presence of H₂O₂, a segment of the Krebs cycle (bold arrows) is maintained by glutamate, which is converted to α-ketoglutarate via transamination. This segment is inhibited only when α-KGDH is also inhibited by ROS. PDH, pyruvate dehydrogenase.

Figure 2

Generation of reactive oxygen species by α-KGDH. Subunit composition of α-KGDH and generation of ROS in the physiological forward reaction of the enzyme, when substrates and cofactors and oxygen are present (a). ROS generation in the forward reaction by α-KGDH is enhanced in the absence of NAD⁺ (b). ROS generation by the E3 subunit induced by NADH in the absence of substrates (c). E1, α-ketoglutarate dehydrogenase; E2, dihydrolipoamide succinyltransferase; E3, dihydrolipoamide dehydrogenase; TPP, thiamine pyrophosphate.