Neuroprotektive Kapazität des Enzyms 2-Oxoglutarat dehydrogenase durch Kontrolle des mitochondrischen Metabolismus

The multienzyme complex 2-oxoglutarate dehydrogenase complex (OGDHC) of mitochondria catalyzes irreversible degradation of 2-oxoglutarate (OG) at the intercept of the glutamate synthesis and energy-producing carbohydrate catabolism. We hypothesize that this knot has a crucial significance for the mitochondria-dependent signaling and neuroprotection due to the signaling function of the OGDHC substrate and glutamate precursor, OG. The aim of this project is to control neuronal death and survival by regulating the flux through OGDHC. Experimental verification of our hypothesis will include: 1. Characterization of the tissue-specific structure, function and regulation of OGDHC isolated from brain; 2. In vitro study of the interaction of brain OGDHC with the catalysis-activated inhibitors, the phosphono analogues of OG; 3. Regulation of OGDHC of neural cells in situ using the phosphono analogues of OG; 4. Study of cellular responses to the impaired OG degradation by OGDHC. The following changes in cellular functions in response to the OGDHC regulation are studied: 1. ATP-production (energy status of cells), 2. glutamate-induced Ca2+ mobilization, 3. change in mitochondrial potential, 4. ROS production. 5. cellular viability. Regulation of isolated brain OGDHC by cellular metabolites, substrates, products, cofactors and protein-protein or protein/lipid interactions will be characterized in order to understand the enzyme function and metabolic regulation within the cellular network. This will be aided by genomic and protein databases analysis through application of bioinformatics approaches. As a result, the potential regulation of OGDHC  in therapy of neurogenerative diseases will be revealed. The project is a collaboration between the Institut für Neurobiochemie in Magdeburg and the Belozersky Institute of the Moscow University.