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The Journal of Neuroscience, September 8, 2004, 24(36):7771-7778; doi:10.1523/JNEUROSCI.1842-04.2004

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Neurobiology of Disease
Generation of Reactive Oxygen Species in the Reaction Catalyzed by -Ketoglutarate Dehydrogenase

Laszlo Tretter and Vera Adam-Vizi

Department of Medical Biochemistry, Semmelweis University, and Neurochemistry Group, Hungarian Academy of Sciences, Budapest H-1444, Hungary

-Ketoglutarate dehydrogenase (-KGDH), a key enzyme in the Krebs' cycle, is a crucial early target of oxidative stress (Tretter and Adam-Vizi, 2000). The present study demonstrates that -KGDH is able to generate H₂O₂ and, thus, could also be a source of reactive oxygen species (ROS) in mitochondria. Isolated -KGDH with coenzyme A (HS-CoA) and thiamine pyrophosphate started to produce H₂O₂ after addition of -ketoglutarate in the absence of nicotinamide adenine dinucleotide-oxidized (NAD⁺). NAD⁺, which proved to be a powerful inhibitor of -KGDH-mediated H₂O₂ formation, switched the H₂O₂ forming mode of the enzyme to the catalytic [nicotinamide adenine dinucleotide-reduced (NADH) forming] mode. In contrast, NADH stimulated H₂O₂ formation by -KGDH, and for this, neither -ketoglutarate nor HS-CoA were required. When all of the substrates and cofactors of the enzyme were present, the NADH/NAD⁺ ratio determined the rate of H₂O₂ production. The higher the NADH/NAD⁺ ratio the higher the rate of H₂O₂ production. H₂O₂ production as well as the catalytic function of the enzyme was activated by Ca²⁺. In synaptosomes, using -ketoglutarate as respiratory substrate, the rate of H₂O₂ production increased by 2.5-fold, and aconitase activity decreased, indicating that -KGDH can generate H₂O₂ in in situ mitochondria. Given the NADH/NAD⁺ ratio as a key regulator of H₂O₂ production by -KGDH, it is suggested that production of ROS could be significant not only in the respiratory chain but also in the Krebs' cycle when oxidation of NADH is impaired. Thus -KGDH is not only a target of ROS but could significantly contribute to generation of oxidative stress in the mitochondria.

Key words: mitochondria; synaptosome; -ketoglutarate dehydrogenase; hydrogen peroxide; oxidative stress; NADH/NAD ratio

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Received May 12, 2004; revised July 7, 2004; accepted July 8, 2004.

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