QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

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

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (37) Citing Articles via Google Scholar Google Scholar Articles by Tretter, L. Articles by Adam-Vizi, V. Search for Related Content PubMed PubMed Citation Articles by Tretter, L. Articles by Adam-Vizi, V.

 Previous Article  |  Next Article 

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

---

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

This article has been cited by other articles:

				V. Kumar, V. Kota, and S. Shivaji Hamster Sperm Capacitation: Role of Pyruvate Dehydrogenase A and Dihydrolipoamide Dehydrogenase Biol Reprod, August 1, 2008; 79(2): 190 - 199. [Abstract] [Full Text] [PDF]

				E. V. Ilieva, V. Ayala, M. Jove, E. Dalfo, D. Cacabelos, M. Povedano, M. J. Bellmunt, I. Ferrer, R. Pamplona, and M. Portero-Otin Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis Brain, December 1, 2007; 130(12): 3111 - 3123. [Abstract] [Full Text] [PDF]

				E. B. Tahara, M. H. Barros, G. A. Oliveira, L. E. S. Netto, and A. J. Kowaltowski Dihydrolipoyl dehydrogenase as a source of reactive oxygen species inhibited by caloric restriction and involved in Saccharomyces cerevisiae aging FASEB J, January 1, 2007; 21(1): 274 - 283. [Abstract] [Full Text] [PDF]

				N. Watanabe, J. W. Zmijewski, W. Takabe, M. Umezu-Goto, C. L. Goffe, A. Sekine, A. Landar, A. Watanabe, J. Aoki, H. Arai, et al. Activation of Mitogen-Activated Protein Kinases by Lysophosphatidylcholine-Induced Mitochondrial Reactive Oxygen Species Generation in Endothelial Cells Am. J. Pathol., May 1, 2006; 168(5): 1737 - 1748. [Abstract] [Full Text] [PDF]

				P. Schonfeld and G. Reiser Rotenone-like Action of the Branched-chain Phytanic Acid Induces Oxidative Stress in Mitochondria J. Biol. Chem., March 17, 2006; 281(11): 7136 - 7142. [Abstract] [Full Text] [PDF]

				F. Di Lisa and P. Bernardi Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition Cardiovasc Res, May 1, 2005; 66(2): 222 - 232. [Abstract] [Full Text] [PDF]

				A. A. Starkov, G. Fiskum, C. Chinopoulos, B. J. Lorenzo, S. E. Browne, M. S. Patel, and M. F. Beal Mitochondrial {alpha}-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species J. Neurosci., September 8, 2004; 24(36): 7779 - 7788. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help