全脑缺血损伤是造成心肺复苏后患者死亡的重要原因，线粒体功能异常在其中发挥重要作用，然而具体分子调控机制仍不够清楚。我们通过蛋白质组学研究发现，苹果酸酶1（ME1）在复苏后的脑线粒体中表达显著升高。ME1催化丙酮酸与苹果酸转化，但它在复苏后全脑缺血损伤中作用及调控机制还不清楚。我们前期研究发现缺氧后的神经细胞中ME1与琥珀酸含量和氧化应激水平有一定关联性。结合文献报道与我们的研究，我们提出科学假设：ME1通过琥珀酸代谢而调控细胞氧化应激水平、表观遗传修饰和线粒体分裂，从而损伤神经功能。本项目将利用细胞和动物模型，在分子、细胞和动物水平上首次揭示ME1在复苏后全脑缺血损伤中发挥的作用及调控机制，研究药物抑制ME1调控的琥珀酸代谢通路对复苏后全脑缺血损伤的保护作用，并分析琥珀酸作为代谢标记物对复苏后全脑缺血损伤的诊断和预后价值。本研究将为复苏后全脑缺血损伤的诊断、预后评价及药物治疗提供新的策略。

Global cerebral ischemic injury is an important cause of death in patients after cardiopulmonary resuscitation. Mitochondrial dysfunction plays an important role in brain jury, but the specific molecular regulation mechanism remains unclear. We have found that malic enzyme 1 (ME1) was significantly elevated in brain mitochondria after resuscitation through proteomics analysis. ME1 catalyzes the conversion of pyruvate and malate, but its role and regulation mechanism in global cerebral ischemia after resuscitation is still unclear. Our previous experiments found that ME1 had a correlation with the succinate and oxidative stress in neurons after hypoxia. Combined with literature reports and our research, we propose a scientific hypothesis that ME1 regulates cellular oxidative stress levels, epigenetic modifications, and mitochondrial fission through succinate metabolism, thereby causing brain injury. This project will to reveal the role and mechanism of ME1 in global cerebral ischemic injury after resuscitation for the first time by using cell and animal models at the molecular, cellular and animal levels. This project will investigate the protective effects of inhibiting ME1-regulated succinate metabolic pathway on global cerebral ischemic injury after resuscitation, and analyze the value of succinate as a metabolic marker in the diagnosis and prognosis of global cerebral ischemic injury after resuscitation. This study will provide new strategies for the diagnosis, prognosis and drug treatment of global cerebral ischemic injury after resuscitation.