Zhang Lina, Li Jiaying, Li Chenglong, Wu Yujin, Liu Shuai, Li Qi, Qi Sihua
Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, 37 Yiyuan Road, Harbin, 150001, Heilongjiang, China.
Mol Neurobiol. 2025 Feb;62(2):2376-2395. doi: 10.1007/s12035-024-04405-z. Epub 2024 Aug 7.
Postoperative cognitive dysfunction (POCD), a common complication following anesthesia and surgery, is influenced by hippocampal neuroinflammation and microglial activation. Mitophagy, a process regulating inflammatory responses by limiting the accumulation of damaged mitochondria, plays a significant role. This study aimed to determine whether regulating microglial mitophagy and the cGAS-STING pathway could alleviate cognitive decline after surgery. Exploratory laparotomy was performed to establish a POCD model using mice. Western blotting, immunofluorescence staining, transmission electron microscopy, and mt-Keima assays were used to examine microglial mitophagy and the cGAS-STING pathway. Quantitative polymerase chain reaction (qPCR) was used to detect inflammatory mediators and cytosolic mitochondrial DNA (mtDNA) levels in BV2 cells. Exploratory laparotomy triggered mitophagy and enhanced the cGAS-STING pathway in mice hippocampi. Pharmacological treatment reduced microglial activation, neuroinflammation, and cognitive impairment after surgery. Mitophagy suppressed the cGAS-STING pathway in mice hippocampi. In vitro, microglia-induced inflammation was mediated by mitophagy and the cGAS-STING pathway. Small interfering RNA (siRNA) of PINK1 hindered mitophagy activation and facilitated the cytosolic release of mtDNA, resulting in the initiation of the cGAS-STING pathway and innate immune response. Microglial mitophagy inhibited inflammatory responses via the mtDNA-cGAS-STING pathway inducing microglial mitophagy and inhibiting the mtDNA-cGAS-STING pathway may be an effective therapeutic approach for patients with POCD.
术后认知功能障碍（POCD）是麻醉和手术后常见的并发症，受海马神经炎症和小胶质细胞激活的影响。线粒体自噬是一种通过限制受损线粒体积累来调节炎症反应的过程，起着重要作用。本研究旨在确定调节小胶质细胞线粒体自噬和cGAS-STING通路是否能减轻术后认知功能下降。通过对小鼠进行剖腹探查术建立POCD模型。采用蛋白质免疫印迹法、免疫荧光染色法、透射电子显微镜法和线粒体Keima检测法检测小胶质细胞线粒体自噬和cGAS-STING通路。采用定量聚合酶链反应（qPCR）检测BV2细胞中炎症介质和细胞溶质线粒体DNA（mtDNA）水平。剖腹探查术触发了小鼠海马体中的线粒体自噬并增强了cGAS-STING通路。药物治疗减少了术后小胶质细胞激活、神经炎症和认知障碍。线粒体自噬抑制了小鼠海马体中的cGAS-STING通路。在体外，小胶质细胞诱导的炎症由线粒体自噬和cGAS-STING通路介导。PINK1的小干扰RNA（siRNA）阻碍了线粒体自噬激活并促进了mtDNA的细胞溶质释放，导致cGAS-STING通路的启动和先天免疫反应。小胶质细胞线粒体自噬通过mtDNA-cGAS-STING通路抑制炎症反应，诱导小胶质细胞线粒体自噬并抑制mtDNA-cGAS-STING通路可能是POCD患者的一种有效治疗方法。
