Succinyl phosphonate is a specific inhibitor of α -ketoglutarate dehydrogenase (α-KGDHC), effective inhibits KGDHC in muscle, bacterial, brain, and cultured human fibroblasts[1]. α-KGDHC is not only the core enzyme of cellular energy metabolism, but also plays an important role in various physiological processes such as antioxidation and gene expression regulation [2]. Succinyl phosphonate is usually used in the research of the mechanisms of oxidative stress and neuroinflammation in neurodegenerative diseases, such Alzheimer's disease and Parkinson's disease [3][4].
In vitro, treatment of NG108-15 cells with Succinyl phosphonate (0.2mM) for 48h drastically increased the release of LDH induced by glutamate and elevated the levels of resting extracellular glutamate[5].
In vivo, intracerebroventricular injection of Succinyl phosphonate(1mg/kg; 24h) in lipopolysaccharide-induced(LPS-induced) microglia mice down-regulated the succinylation levels, reduced ROS production and improved lipid metabolism, and ameliorated MG senescence[6]. Administration of Succinyl phosphonate(0.02mmol/kg; intranasally; 24h) in rats significantly decreased levels of either citrulline or carnosine and increased the activities of OGDHC and malate dehydrogenase[7].
References:
[1] Biryukov, A. I., Bunik, V. I., Zhukov, Y. N., Khurs, E. N., & Khomutov, R. M. (1996). Succinyl phosphonate inhibits alpha-ketoglutarate oxidative decarboxylation, catalyzed by alpha-ketoglutarate dehydrogenase complexes from E. coli and pigeon breast muscle. FEBS letters, 382(1-2), 167–170.
[2] Tretter, L., & Adam-Vizi, V. (2005). Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 360(1464), 2335–2345.
[3] Trofimova, L., Lovat, M., Groznaya, A., Efimova, E., Dunaeva, T., Maslova, M., Graf, A., & Bunik, V. (2010). 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. International journal of Alzheimer's disease, 2010, 749061.
[4] Sayehmiri, F., Khodagholi, F., Pourbadie, H. G., Naderi, N., Aliakbarzadeh, F., Hashemi, R., Naderi, S., & Motamedi, F. (2022). Phosphonate analog of 2-oxoglutarate regulates glutamate-glutamine homeostasis and counteracts amyloid beta induced learning and memory deficits in rats. Experimental gerontology, 168, 111944.
[5] Weidinger, A., Milivojev, N., Hosmann, A., Duvigneau, J. C., Szabo, C., Törö, G., Rauter, L., Vaglio-Garro, A., Mkrtchyan, G. V., Trofimova, L., Sharipov, R. R., Surin, A. M., Krasilnikova, I. A., Pinelis, V. G., Tretter, L., Moldzio, R., Bayır, H., Kagan, V. E., Bunik, V. I., & Kozlov, A. V. (2023). Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death. Redox biology, 62, 102669.
[6] Zhao, X., Yang, X., Du, C., Hao, H., Liu, S., Liu, G., Zhang, G., Fan, K., & Ma, J. (2024). Up-regulated succinylation modifications induce a senescence phenotype in microglia by altering mitochondrial energy metabolism. Journal of neuroinflammation, 21(1), 296.
[7] Bunik, V. I., Artiukhov, A. V., Kazantsev, A. V., Aleshin, V. A., Boyko, A. I., Ksenofontov, A. L., Lukashev, N. V., & Graf, A. V. (2022). Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses. Frontiers in chemistry, 10, 892284.