Role of 2-oxoglutarate dehydrogenase in brain pathologies involving glutamate neurotoxicity

Граф, А. В.; Kabysheva, Maria S.; Klimuk, Evgeny; Trofimova, L. K.; Dunaeva, T. Yu.; Zündorf, Gregor; Kahlert, Stefan; Reiser, Georg; Storozhevykh, T. P.; Pinelis, V. G.; Sokolova, N. I.; Bunik, Victoria I.

doi:10.1016/j.molcatb.2009.02.016

Cited by 23 publications

(30 citation statements)

References 40 publications

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“…In our earlier work on the developmental impact of the brain OGDHC activity, we observed the sex-determined differences in the brain OGDHC expression and reactivity to SP [21]. The present study confirms dependence of the behavioral impact of the OGDHC regulation on the animal physiology, as behavior of pregnant females is less responsive to SP than that of males.…”

Section: Discussionsupporting

confidence: 87%

“…In cellular experiments, SP was shown to protect from the glutamate-induced ROS [18] and excitotoxicity [16, 17, 21]. Owing to this, we tested if SP would show a protective action on the behavioral and biochemical changes induced by hypoxia.…”

Section: Resultsmentioning

confidence: 99%

“…OGDHC activity was extracted and assayed as described earlier [21]. Each sample corresponded to one animal, with the OGDHC assay in a sample repeated 3-4 times at three different protein concentrations.…”

Section: Methodsmentioning

confidence: 99%

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Behavioral Impact of the Regulation of the Brain 2-Oxoglutarate Dehydrogenase Complex by Synthetic Phosphonate Analog of 2-Oxoglutarate: Implications into the Role of the Complex in Neurodegenerative Diseases

Trofimova

Lovat

Groznaya

et al. 2010

International Journal of Alzheimer's Disease

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Decreased activity of the mitochondrial 2-oxoglutarate dehydrogenase complex (OGDHC) in brain accompanies neurodegenerative diseases. To reveal molecular mechanisms of this association, we treated rats with a specific inhibitor of OGDHC, succinyl phosphonate, or exposed them to hypoxic stress. In males treated with succinyl phosphonate and in pregnancy-sensitized females experiencing acute hypobaric hypoxia, we revealed upregulation of brain OGDHC (within 24 hours), with the activity increase presumably representing the compensatory response of brain to the OGDHC inhibition. This up-regulation of brain OGDHC was accompanied by an increase in exploratory activity and a decrease in anxiety of the experimental animals. Remarkably, the hypoxia-induced elevation of brain OGDHC and most of the associated behavioral changes were abrogated by succinyl phosphonate. The antagonistic action of hypoxia and succinyl phosphonate demonstrates potential therapeutic significance of the OGDHC regulation by the phosphonate analogs of 2-oxoglutarate.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

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Behavioral Impact of the Regulation of the Brain 2-Oxoglutarate Dehydrogenase Complex by Synthetic Phosphonate Analog of 2-Oxoglutarate: Implications into the Role of the Complex in Neurodegenerative Diseases

Trofimova

Lovat

Groznaya

et al. 2010

International Journal of Alzheimer's Disease

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“…OGDHc is not only a source but also a sensitive target of reactive oxygen species (ROS) in mitochondria [5,38–41]; hypoxia-and glutamate-induced cerebral damage was strongly linked to the inactivation of OGDHc [34]. The mammalian PDHc was demonstrated to be a much weaker ROS generator compared to OGDHc [7,11,13]; the reason for this still appears obscure [13,36,42].…”

Section: Introductionmentioning

confidence: 99%

Formation of reactive oxygen species by human and bacterial pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes reconstituted from recombinant components

Ambrus

Nemeria

Törőcsik

et al. 2015

Free Radical Biology and Medicine

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Individual recombinant components of pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes (PDHc, OGDHc) of human and Escherichia coli (E. coli) origin were expressed and purified from E. coli with optimized protocols. The four multienzyme complexes were each reconstituted under optimal conditions at different stoichiometric ratios. Binding stoichiometries for the highest catalytic efficiency were determined from the rate of NADH generation by the complexes at physiological pH. Since some of these complexes were shown to possess ‘moonlighting’ activities under pathological conditions often accompanied by acidosis, activities were also determined at pH 6.3. As reactive oxygen species (ROS) generation by the E3 component of hOGDHc is a pathologically relevant feature, superoxide generation by the complexes with optimal stoichiometry was measured by the acetylated cytochrome c reduction method in both the forward and the reverse catalytic directions. Various known affectors of physiological activity and ROS production, including Ca2+, ADP, lipoylation status or pH, were investigated. The human complexes were also reconstituted with the most prevalent human pathological mutant of the E3 component, G194C and characterized; isolated human E3 with the G194C substitution was previously reported to have an enhanced ROS generating capacity. It is demonstrated that: i. PDHc, similarly to OGDHc, is able to generate ROS and this feature is displayed by both the E. coli and human complexes, ii. Reconstituted hPDHc generates ROS at a significantly higher rate as compared to hOGDHc in both the forward and the reverse reactions when ROS generation is calculated for unit mass of their common E3 component, iii. The E1 component or E1-E2 subcomplex generates significant amount of ROS only in hOGDHc; iv. Incorporation of the G194C variant of hE3, the result of a disease-causing mutation, into reconstituted hOGDHc and hPDHc indeed leads to a decreased activity of both complexes and higher ROS generation by only hOGDHc and only in its reverse reaction.

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“…Because glutamate excitotoxicity is known to contribute greatly to hypoxic–ischemic damage to both adult and developing brain, we tested analogs of KG in vivo as neuroprotective agents, using a model of prenatal hypoxia. Exposure of pregnant rats to KG analogs was shown to alleviate hypoxic damage to their offspring (113). It is worth noting that the glutamate neurotoxicity observed in neurodegenerative diseases is associated with increased ROS production in overstimulated neurons (114).…”

Section: Potential Role Of Paracatalytic Side Reactions In Disementioning

confidence: 99%

A Survey of Oxidative Paracatalytic Reactions Catalyzed by Enzymes that Generate Carbanionic Intermediates: Implications for ROS Production, Cancer Etiology, and Neurodegenerative Diseases

Bunik

Schloss

Pinto

et al. 2011

Advances in Enzymology - And Related Areas of Molecular Biology

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Role of 2-oxoglutarate dehydrogenase in brain pathologies involving glutamate neurotoxicity

Cited by 23 publications

References 40 publications

Behavioral Impact of the Regulation of the Brain 2-Oxoglutarate Dehydrogenase Complex by Synthetic Phosphonate Analog of 2-Oxoglutarate: Implications into the Role of the Complex in Neurodegenerative Diseases

Behavioral Impact of the Regulation of the Brain 2-Oxoglutarate Dehydrogenase Complex by Synthetic Phosphonate Analog of 2-Oxoglutarate: Implications into the Role of the Complex in Neurodegenerative Diseases

Formation of reactive oxygen species by human and bacterial pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes reconstituted from recombinant components

A Survey of Oxidative Paracatalytic Reactions Catalyzed by Enzymes that Generate Carbanionic Intermediates: Implications for ROS Production, Cancer Etiology, and Neurodegenerative Diseases

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