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

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216 Citations (Scopus)

Abstract

Alpha-ketoglutarate dehydrogenase (α-KGDH) is a highly regulated enzyme, which could determine the metabolic flux through the Krebs cycle. It catalyses the conversion of α-ketoglutarate to succinyl-CoA and produces NADH directly providing electrons for the respiratory chain. α-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 α-KGDH to ROS but as long as α-KGDH is functional NADH generation in the Krebs cycle is maintained. NADH supply to the respiratory chain is limited only when α-KGDH is also inhibited by ROS. In addition being a key target, α-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 α-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.

Original languageEnglish
Pages (from-to)2335-2345
Number of pages11
JournalPhilosophical Transactions of the Royal Society B: Biological Sciences
Volume360
Issue number1464
DOIs
Publication statusPublished - Dec 29 2005

Keywords

  • Alpha-ketoglutarate dehydrogenase
  • Mitochondria
  • Neurodegeneration
  • Oxidative stress
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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