ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2004
Generation of reactive oxygen species in the reaction catalyzed by alpha-ketoglutarate dehydrogenase.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 196 papers.
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196 citing papers in PubMed, 445 citations in OpenAlex.
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- Metabolic Remodeling of the Tricarboxylic Acid Cycle and Glycolysis Reveals Cold-Induced Respiratory Adaptations inInsects · 2025Article
- Targeted Redox Regulation α-Ketoglutarate Dehydrogenase Complex for the Treatment of Human Diseases.Cells · 2025Review
- Enzyme-modified microelectrodes for measurement of glutamate: Characterization and applications.Electroanalysis · 2025Article
- Parkinson's disease and glucose metabolism impairment.Translational neurodegeneration · 2025Review
- ROSBASE1.0: a comprehensive database of reactive oxygen species (ROS): categorization of cell organelles, proteins, taxonomy, and diseases based on ROS-related activities.Database : the journal of biological databases and curation · 2025Article
- α-Ketoisocaproic Acid Disrupts Mitochondrial Bioenergetics in the Brain of Neonate Rats: Molecular Modeling Studies of α-ketoglutarate Dehydrogenase Subunits Inhibition.Neurochemical research · 2025Article
- The Role of Cuproptosis in Hyperoxia-Induced Lung Injury and Its Potential for Treatment.Journal of inflammation research · 2025Article
- Molecular architecture of the mammalian 2-oxoglutarate dehydrogenase complex.Nature communications · 2024Article
- Mitochondria-Associated Membranes in Aging and Senescence.Aging and disease · 2024Review
- Role of mitochondria in neonatal hypoxic-ischemic encephalopathy.Histology and histopathology · 2024Review
- Metabolomics Analysis of Rabbit Plasma after Ocular Exposure to Vapors of Sulfur Mustard.Metabolites · 2024Article
- A Consolidated Understanding of the Contribution of Redox Dysregulation in the Development of Hearing Impairment.Antioxidants (Basel, Switzerland) · 2024Review
- Fluoride-Induced Mitochondrial Dysfunction and Approaches for Its Intervention.Biological trace element research · 2024Review
136 more citing papers are in PubMed but not listed here.
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2 authors at 2 institutions in 1 country.
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Abstract
Alpha-ketoglutarate dehydrogenase (alpha-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 alpha-KGDH is able to generate H(2)O(2) and, thus, could also be a source of reactive oxygen species (ROS) in mitochondria. Isolated alpha-KGDH with coenzyme A (HS-CoA) and thiamine pyrophosphate started to produce H(2)O(2) after addition of alpha-ketoglutarate in the absence of nicotinamide adenine dinucleotide-oxidized (NAD(+)). NAD(+), which proved to be a powerful inhibitor of alpha-KGDH-mediated H(2)O(2) formation, switched the H(2)O(2) forming mode of the enzyme to the catalytic [nicotinamide adenine dinucleotide-reduced (NADH) forming] mode. In contrast, NADH stimulated H(2)O(2) formation by alpha-KGDH, and for this, neither alpha-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 H(2)O(2) production. The higher the NADH/NAD(+) ratio the higher the rate of H(2)O(2) production. H(2)O(2) production as well as the catalytic function of the enzyme was activated by Ca(2+). In synaptosomes, using alpha-ketoglutarate as respiratory substrate, the rate of H(2)O(2) production increased by 2.5-fold, and aconitase activity decreased, indicating that alpha-KGDH can generate H(2)O(2) in in situ mitochondria. Given the NADH/NAD(+) ratio as a key regulator of H(2)O(2) production by alpha-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 alpha-KGDH is not only a target of ROS but could significantly contribute to generation of oxidative stress in the mitochondria.
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