2-Oxosuccinic acid is an α-keto acid that reacts with acetyl-CoA and water to form citrate in the first step of the citric acid cycle and is regenerated by oxidation of L-malate in the last step[1]. 2-Oxosuccinic acid is a metabolic intermediate formed by the carboxylation of pyruvate in mitochondria, followed by decarboxylation and phosphorylation to form phosphoenolpyruvate[2]. 2-Oxosuccinic acid can effectively inhibit succinate dehydrogenase (SDH) at a concentration of 5µM[3]. 2-Oxosuccinic acid has a neuroprotective effect and reduces brain and blood glutamate levels by activating the blood-resident enzyme glutamate-oxaloacetate transaminase [4].
In vitro, 2-Oxosuccinic acid (50mM) treatment of HepG2 cells for 12h and 24h significantly reduced the mRNA and protein expression of HIF1α and c-myc, reduced Akt phosphorylation, and inhibited the Akt/HIF pathway in cells[5]. 2-Oxosuccinic acid (10 mM) treatment of LO-2 cells for 24 h can remove ROS, reduce oxidative damage caused by H2O2, maintain the integrity of mitochondrial structure, and increase ATP production[6].
In vivo, 2-Oxosuccinic acid (10 mg/kg) was used to treat paraquat-poisoned mice by intraperitoneal injection for 3 days, which significantly improved the survival rate of mice, alleviated the poisoning state, reduced the wet weight/dry weight ratio of the mouse lungs, and reduced the pathological damage of lung tissues[7].
References:
[1] Frizzell N. 10 CHAPTER The Tricarboxylic Acid Cycle[J]. Medical Biochemistry-E-Book: Medical Biochemistry-E-Book, 2022: 129.
[2] Jitrapakdee S, St Maurice M, Rayment I, et al. Structure, mechanism and regulation of pyruvate carboxylase[J]. Biochemical journal, 2008, 413(3): 369-387.
[3] Fink B D, Bai F, Yu L, et al. Oxaloacetic acid mediates ADP-dependent inhibition of mitochondrial complex II–driven respiration[J]. Journal of Biological Chemistry, 2018, 293(51): 19932-19941.
[4] Campos F, Sobrino T, Ramos-Cabrer P, et al. Oxaloacetate: a novel neuroprotective for acute ischemic stroke[J]. The international journal of biochemistry & cell biology, 2012, 44(2): 262-265.
[5] Kuang Y, Han X, Xu M, et al. Oxaloacetate induces apoptosis in HepG2 cells via inhibition of glycolysis[J]. Cancer medicine, 2018, 7(4): 1416-1429.
[6] Kuang Y, Han X, Xu M, et al. Oxaloacetate ameliorates chemical liver injury via oxidative stress reduction and enhancement of bioenergetic fluxes[J]. International journal of molecular sciences, 2018, 19(6): 1626.
[7] Li W, Li M, Chen K, et al. Oxaloacetate acid ameliorates paraquat-induced acute lung injury by alleviating oxidative stress and mitochondrial dysfunction[J]. Frontiers in Pharmacology, 2022, 13: 1029775.
2-Oxosuccinic acid（草酰乙酸）是一种α-酮酸，在柠檬酸循环的第一步中草酰乙酸与乙酰辅酶A和水反应形成柠檬酸盐，并在最后一步中通过L-苹果酸的氧化再生[1]。2-Oxosuccinic acid是线粒体内丙酮酸羧化形成的代谢中间体，随后脱羧和磷酸化形成磷酸烯醇丙酮酸[2]。2-Oxosuccinic acid可在5µM浓度下有效抑制琥珀酸脱氢酶（SDH）[3]。2-Oxosuccinic acid具有神经保护作用，通过激活血液驻留酶谷氨酸-草酰乙酸转氨酶而降低大脑和血液谷氨酸水平[4]。
在体外，2-Oxosuccinic acid（50mM）处理HepG2细胞12h和24h，显著降低了HIF1α和c-myc的mRNA和蛋白表达，减少了Akt磷酸化，抑制了细胞中的Akt/HIF通路[5]。2-Oxosuccinic acid（10mM）处理LO-2细胞24 h，能清除ROS，减轻了H2O2引起的氧化损伤，维持线粒体结构的完整性，增加了ATP的生产[6]。
在体内，2-Oxosuccinic acid（10mg/kg）通过腹腔注射治疗百草枯中毒小鼠3天，显著提高小鼠生存率，缓解中毒状态，降低小鼠肺脏湿重/干重比，减轻肺组织病理学损伤[7]。