Mkrtchyan Garik V, Graf Anastasia, Trofimova Lidia, Ksenofontov Alexander, Baratova Ludmila, Bunik Victoria
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Leninskije gori 1, 119992, Moscow, Russia.
Faculty of Biology, Lomonosov Moscow State University, Leninskije gori 1, 119992, Moscow, Russia; Faculty of Nano-, Bio-, Informational and Cognitive Technologies at Moscow Institute of Physics and Technology, Maximova Street, 4, 123098, Moscow, Russia.
Anal Biochem. 2018 Jul 1;552:100-109. doi: 10.1016/j.ab.2018.01.003. Epub 2018 Jan 8.
Glutamate is a key metabolite and major excitatory neurotransmitter, degraded through transformation to 2-oxoglutarate which is further catabolized by 2-oxoglutarate dehydrogenase complex (OGDHC). Both the glutamate excitotoxicity and impaired OGDHC activity are hallmarks of neurodegeneration. This work quantifies a relationship between the brain OGDHC activity and glutamate levels, assessing its diagnostic value to characterize (patho)physiology. A moderate to strong positive correlation of the two parameters determined under varied physiological settings (brain regions, seasons, gender, pregnancy, rat line), is revealed. Mitochondrial impairment (OGDHC inhibition or acute hypobaric hypoxia) decreases the interdependence, even when the parameter means do not change significantly. Compared to the cortex, the cerebellum exhibits a lower inter-individual glutamate variation and a weaker glutamate-OGDHC interdependence. Specific metabolism of the brain regions is also characterized by a positive correlation between glutamate and γ-aminobutyric acid (GABA) concentrations in the cortex but not in the cerebellum. In contrast, a strong positive correlation between glutamate and glutamine is present in both the cortex and cerebellum. The differences in metabolic correlations are in line with transcriptomics data which suggest that glutamate distribution between competitive pathways contributes to the brain-region-specific features of the interdependences of glutamate and OGDHC or GABA.
谷氨酸是一种关键代谢物和主要兴奋性神经递质，通过转化为2-氧代戊二酸进行降解，2-氧代戊二酸进一步由2-氧代戊二酸脱氢酶复合体（OGDHC）进行分解代谢。谷氨酸兴奋性毒性和OGDHC活性受损均为神经退行性变的特征。这项工作量化了脑OGDHC活性与谷氨酸水平之间的关系，评估其对表征（病理）生理学的诊断价值。结果显示，在不同生理条件（脑区、季节、性别、妊娠、大鼠品系）下测定的这两个参数之间存在中度至强的正相关。线粒体损伤（OGDHC抑制或急性低压缺氧）会降低这种相互依赖性，即使参数均值没有显著变化。与皮质相比，小脑的个体间谷氨酸变化较小，谷氨酸与OGDHC的相互依赖性较弱。脑区的特定代谢还表现为皮质中谷氨酸与γ-氨基丁酸（GABA）浓度呈正相关，而小脑中则不然。相反，皮质和小脑中谷氨酸与谷氨酰胺之间均存在强正相关。代谢相关性的差异与转录组学数据一致，这些数据表明，竞争性途径之间的谷氨酸分布有助于谷氨酸与OGDHC或GABA相互依赖性的脑区特异性特征。
