DOI: 10.1523/jneurosci.1842-04.2004. Generation of Reactive Oxygen Species in the Reaction Catalyzed by α-Ketoglutarate Dehydrogenase

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

10.1523/jneurosci.1842-04.2004

Crossref journal-article

Society for Neuroscience

The Journal of Neuroscience (393)

Abstract

α-Ketoglutarate dehydrogenase (α-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 α-KGDH is able to generate H2O2and, thus, could also be a source of reactive oxygen species (ROS) in mitochondria. Isolated α-KGDH with coenzyme A (HS-CoA) and thiamine pyrophosphate started to produce H2O2after addition of α-ketoglutarate in the absence of nicotinamide adenine dinucleotide-oxidized (NAD+). NAD+, which proved to be a powerful inhibitor of α-KGDH-mediated H2O2formation, switched the H2O2forming mode of the enzyme to the catalytic [nicotinamide adenine dinucleotide-reduced (NADH) forming] mode. In contrast, NADH stimulated H2O2formation by α-KGDH, and for this, neither α-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 H2O2production. The higher the NADH/NAD+ratio the higher the rate of H2O2production. H2O2production as well as the catalytic function of the enzyme was activated by Ca2+. In synaptosomes, using α-ketoglutarate as respiratory substrate, the rate of H2O2production increased by 2.5-fold, and aconitase activity decreased, indicating that α-KGDH can generate H2O2inin situmitochondria. Given the NADH/NAD+ratio as a key regulator of H2O2production by α-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 α-KGDH is not only a target of ROS but could significantly contribute to generation of oxidative stress in the mitochondria.

Bibliography

Tretter, L., & Adam-Vizi, V. (2004). Generation of Reactive Oxygen Species in the Reaction Catalyzed by Î±-Ketoglutarate Dehydrogenase. The Journal of Neuroscience, 24(36), 7771â7778.

Authors 2

Laszlo Tretter (first)
Vera Adam-Vizi (additional)

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Dates

Type	When
Created	20 years, 11 months ago (Sept. 8, 2004, 3:13 p.m.)
Deposited	1 year, 7 months ago (Jan. 14, 2024, 4:35 a.m.)
Indexed	6 days, 23 hours ago (Aug. 24, 2025, 7:02 p.m.)
Issued	20 years, 11 months ago (Sept. 8, 2004)
Published	20 years, 11 months ago (Sept. 8, 2004)
Published Online	20 years, 11 months ago (Sept. 8, 2004)
Published Print	20 years, 11 months ago (Sept. 8, 2004)

Funders 0

None

BibTeX

@article{Tretter_2004, title={Generation of Reactive Oxygen Species in the Reaction Catalyzed by α-Ketoglutarate Dehydrogenase}, volume={24}, ISSN={1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.1842-04.2004}, DOI={10.1523/jneurosci.1842-04.2004}, number={36}, journal={The Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Tretter, Laszlo and Adam-Vizi, Vera}, year={2004}, month=sep, pages={7771–7778} }

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