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

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• 作者：Anastasia Graf ; Maria Kabysheva ; Eugeny Klimuk ; Lidia Trofimova ; Tatiana Dunaeva ; Gregor Zü ; ndorf ; Stefan Kahlert ; Georg Reiser ; Tatiana Storozhevykh ; Vsevolod Pinelis ; Natalia Sokolova ; Victoria
• 关键词：Glutamate ; Hypoxia ; 2-Oxoglutarate dehydrogenase ; Phosphonate analog of 2-oxoglutarate ; Sexual differentiation
• 刊名：Journal of Molecular Catalysis B: Enzymatic
• 出版年：2009
• 出版时间：November 2009
• 年：2009
• 卷：61
• 期：1-2
• 页码：80-87
• 全文大小：667 K

文摘

Decreased activity of the mitochondrial thiamin-dependent 2-oxoglutarate dehydrogenase complex (OGDHC) is associated with a number of inborn and acquired neuropathologies. We hypothesized that perturbation in flux through the complex influences brain development and function, in particular, because the OGDHC reaction is linked to the synthesis/degradation of neurotransmitters glutamate and GABA. Developmental impact of this metabolic knot was studied by characterizing the brain OGDHC activity in offspring of rats exposed to acute hypobaric hypoxia at a critical organogenesis period of pregnancy. In this model, we detected the hypoxia-induced changes in the brain OGDHC activity and in certain physiologic and morphometric parameters. The changes were mostly abrogated by application of specific effector of cellular OGDHC, the phosphonate analog of 2-oxoglutarate (succinyl phosphonate), shortly before hypoxia. The glutamate excitotoxicity known to greatly contribute to hypoxic damage was alleviated by succinyl phosphonate in situ. That is, the delayed calcium deregulation, mitochondrial depolarization and reactive oxygen species (ROS) production became less pronounced in cultivated neurons loaded with succinyl phosphonate. In vitro, succinyl phosphonate protected OGDHC from the catalysis-induced inactivation. Thus, the protective effects of the phosphonate upon hypoxic insult in vivo may result from the preservation of mitochondrial function and Ca²⁺ homeostasis due to the phosphonate inhibition of both the OGDHC-dependent ROS production and associated OGDHC inactivation. As a result, we showed for the first time that the hypoxia- and glutamate-induced cerebral damage is linked to the function of OGDHC, introducing the phosphonate analogs of 2-oxoglutarate as promising diagnostic tools to reveal the role of OGDHC in brain function and development.