Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi'an, 710032, Shaanxi, China.
Department of Anesthesiology, The 986th Air Force Hospital, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
Mol Brain. 2023 Apr 25;16(1):36. doi: 10.1186/s13041-023-01024-y.
Increasing evidence indicates the major role of mitochondrial function in neurodegenerative disease. However, it is unclear whether mitochondrial dynamics directly affect postoperative neurocognitive disorder (PND). This study aimed to analyze the underlying mechanisms of mitochondrial dynamics in the pathogenesis of PND. Tibial fracture surgery was performed in elderly mice to generate a PND model in vivo. Cognitive behavior was evaluated 3 days post-surgery using novel object recognition and fear conditioning. A gradual increase in the SOX2OT mRNA level and decrease in the SOX2 mRNA level were noted, with impaired cognitive function, in the mice 3 days after tibial surgery compared with mice in the sham group. To evaluate the role of SOX2OT in PND, SOX2OT knockdown was performed in vitro and in vivo using lentivirus transfection in HT22 cells and via brain stereotactic injection of lentivirus, respectively. SOX2OT knockdown reduced apoptosis, inhibited oxidative stress, suppressed mitochondrial hyperdivision, attenuated surgery-induced cognitive dysfunction, and promoted downstream SOX2 expression in elderly mice. Furthermore, Sox2 alleviated mitochondrial functional damage by inhibiting the transcription of mitochondrial division protein Drp1. Our study findings indicate that SOX2OT knockout alleviates surgery-induced mitochondrial fission and cognitive function defects by upregulating the expression of Sox2 in mice, resulting in the inhibition of drp1 transcription. Therefore, regulation of the SOX2/Drp1 pathway may be a potential mechanism for the treatment of patients with PND.
越来越多的证据表明线粒体功能在神经退行性疾病中起着重要作用。然而，线粒体动力学是否直接影响术后神经认知障碍（PND）尚不清楚。本研究旨在分析线粒体动力学在 PND 发病机制中的潜在机制。在老年小鼠中进行胫骨骨折手术，在体内产生 PND 模型。术后 3 天使用新物体识别和恐惧条件反射评估认知行为。与假手术组相比，胫骨手术后 3 天，小鼠的 SOX2OT mRNA 水平逐渐升高，SOX2 mRNA 水平降低，认知功能受损。为了评估 SOX2OT 在 PND 中的作用，分别通过慢病毒转染在 HT22 细胞中和通过脑立体定位注射慢病毒在体外和体内进行 SOX2OT 敲低。SOX2OT 敲低可减少细胞凋亡，抑制氧化应激，抑制线粒体过度分裂，减轻老年小鼠手术引起的认知功能障碍，并促进下游 SOX2 的表达。此外，Sox2 通过抑制线粒体分裂蛋白 Drp1 的转录来减轻线粒体功能损伤。我们的研究结果表明，SOX2OT 敲除通过上调小鼠 Sox2 的表达减轻手术引起的线粒体分裂和认知功能缺陷，从而抑制 drp1 转录。因此，调节 SOX2/Drp1 通路可能是治疗 PND 患者的潜在机制。
