Abstract：
BACKGROUND: Neuroinflammation is crucial in the development of postoperative cognitive dysfunction (POCD), and microglial activation is an active participant in this process. SS-31, a mitochondrion-targeted antioxidant, is widely regarded as a potential drug for neurodegenerative diseases and inflammatory diseases. In this study, we sought to explore whether SS-31 plays a neuroprotective role and the underlying mechanism.
METHODS: Internal fixation of tibial fracture was performed in 18-month-old mice to induce surgery-associated neurocognitive dysfunction. LPS was administrated to BV2 cells to induce neuroinflammation. Neurobehavioral deficits, hippocampal injury, protein expression, mitophagy level and cell state were evaluated after treatment with SS-31, PHB2 siRNA and an STING agonist.
RESULTS: Our study revealed that SS-31 interacted with PHB2 to activate mitophagy and improve neural damage in surgically aged mice, which was attributed to the reduced cGAS-STING pathway and M1 microglial polarization by decreased release of mitochondrial DNA (mtDNA) but not nuclear DNA (nDNA). In vitro, knockdown of PHB2 and an STING agonist abolished the protective effect of SS-31.
CONCLUSIONS: SS-31 conferred neuroprotection against POCD by promoting PHB2-mediated mitophagy activation to inhibit mtDNA release, which in turn suppressed the cGAS-STING pathway and M1 microglial polarization.
METHODS: Internal fixation of tibial fracture was performed in 18-month-old mice to induce surgery-associated neurocognitive dysfunction. LPS was administrated to BV2 cells to induce neuroinflammation. Neurobehavioral deficits, hippocampal injury, protein expression, mitophagy level and cell state were evaluated after treatment with SS-31, PHB2 siRNA and an STING agonist.
RESULTS: Our study revealed that SS-31 interacted with PHB2 to activate mitophagy and improve neural damage in surgically aged mice, which was attributed to the reduced cGAS-STING pathway and M1 microglial polarization by decreased release of mitochondrial DNA (mtDNA) but not nuclear DNA (nDNA). In vitro, knockdown of PHB2 and an STING agonist abolished the protective effect of SS-31.
CONCLUSIONS: SS-31 conferred neuroprotection against POCD by promoting PHB2-mediated mitophagy activation to inhibit mtDNA release, which in turn suppressed the cGAS-STING pathway and M1 microglial polarization.
摘要：
背景：神经炎症在术后认知功能障碍（POCD）的发展中至关重要，小胶质细胞激活是这一过程的积极参与者。SS-31，一种线粒体靶向抗氧化剂，被广泛认为是治疗神经退行性疾病和炎症性疾病的潜在药物。在这项研究中,我们试图探讨SS-31是否发挥神经保护作用及其潜在机制.
方法：对18月龄小鼠进行胫骨骨折内固定，以诱导手术相关的神经认知功能障碍。向BV2细胞施用LPS以诱导神经炎症。神经行为缺陷,海马损伤,蛋白质表达，在用SS-31、PHB2siRNA和STING激动剂处理后评估线粒体自噬水平和细胞状态。
结果：我们的研究表明，SS-31与PHB2相互作用以激活线粒体自噬并改善手术老年小鼠的神经损伤，这归因于cGAS-STING途径的减少和M1小胶质细胞极化，原因是线粒体DNA（mtDNA）而不是核DNA（nDNA）的释放减少。体外，PHB2和STING激动剂的敲减消除了SS-31的保护作用。
结论：SS-31通过促进PHB2介导的线粒体自噬激活以抑制mtDNA释放而赋予针对POCD的神经保护作用，这反过来又抑制了cGAS-STING途径和M1小胶质细胞极化。
方法：对18月龄小鼠进行胫骨骨折内固定，以诱导手术相关的神经认知功能障碍。向BV2细胞施用LPS以诱导神经炎症。神经行为缺陷,海马损伤,蛋白质表达，在用SS-31、PHB2siRNA和STING激动剂处理后评估线粒体自噬水平和细胞状态。
结果：我们的研究表明，SS-31与PHB2相互作用以激活线粒体自噬并改善手术老年小鼠的神经损伤，这归因于cGAS-STING途径的减少和M1小胶质细胞极化，原因是线粒体DNA（mtDNA）而不是核DNA（nDNA）的释放减少。体外，PHB2和STING激动剂的敲减消除了SS-31的保护作用。
结论：SS-31通过促进PHB2介导的线粒体自噬激活以抑制mtDNA释放而赋予针对POCD的神经保护作用，这反过来又抑制了cGAS-STING途径和M1小胶质细胞极化。
