He Keqiang, Zhang Juan, Zhang Wei, Wang Sheng, Li Dingfeng, Ma Xiaolin, Wu Xiaofan, Chai Xiaoqing, Liu Qiang
Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Front Aging Neurosci. 2022 Feb 9;14:772066. doi: 10.3389/fnagi.2022.772066. eCollection 2022.
Perioperative neurocognitive disorders (PNDs) are a type of cognitive dysfunction occurring with a higher incidence in elderly patients. However, the pathological mechanism of PND and effective treatment remain elusive. We generated a PND mouse model by providing wild-type mice with surgical trauma; in our case, we used tibial fracture to investigate PND pathology. Mice aged 7-8 months were randomly divided into two groups: the surgery (tibial fracture) group and the control (sham) group. All mice were subjected to anesthesia. We examined the transcriptome-wide response in the hippocampus, a brain region that is tightly associated with memory formation, of control mice and mice subjected to surgical trauma at day 1 and day 3 after the surgical procedure. We observed reduced transcript levels of respiratory complex components as early as day 1 after surgery, and subsequent protein changes were found at day 3 after surgical trauma. Consequently, the activities of respiratory complexes were reduced, and adenosine triphosphate (ATP) production was decreased in the hippocampus of mice with surgical operations, supporting that respiratory chain function was impaired. In support of these conclusions, the mitochondrial membrane potential (MMP) levels were decreased, and the reactive oxygen species (ROS) levels were significantly increased. Mechanistically, we demonstrated that surgery induced a significant increase in cytokine IL-1β levels at day 1 after surgery, which concomitantly occurred with transcript changes in respiratory complex components. We further uncovered that transcription factors PGC-1α and NRF-1 were responsible for the observed transcript changes in mitochondrial complex components. Importantly, HT22 cells treated with the cytokine IL-1β resulted in similar reductions in PGC-1α and NRF-1, leading to a reduction of both the transcript and protein levels of respiratory complex subunits. Consequently, respiratory function was impaired in HT22 cells treated with IL-1β. Taken together, we demonstrated that reductions in respiratory complex components and subsequent impairment in mitochondrial functions serve as a novel mechanism for PND pathology, providing a potential therapeutic target for PND treatment.
围手术期神经认知障碍（PNDs）是一种在老年患者中发病率较高的认知功能障碍。然而，PND的病理机制和有效治疗方法仍不清楚。我们通过给野生型小鼠施加手术创伤建立了PND小鼠模型；在本研究中，我们采用胫骨骨折来研究PND的病理。将7 - 8月龄的小鼠随机分为两组：手术（胫骨骨折）组和对照组（假手术组）。所有小鼠均接受麻醉。我们在手术后第1天和第3天检测了对照组小鼠和接受手术创伤小鼠海马体（一个与记忆形成密切相关的脑区）的全转录组反应。我们观察到，早在手术后第1天呼吸复合体成分的转录水平就降低了，并且在手术创伤后第3天发现了随后的蛋白质变化。因此，手术小鼠海马体中呼吸复合体的活性降低，三磷酸腺苷（ATP）生成减少，这支持了呼吸链功能受损。为支持这些结论，线粒体膜电位（MMP）水平降低，活性氧（ROS）水平显著升高。从机制上讲，我们证明手术在术后第1天导致细胞因子白细胞介素 - 1β水平显著升高，这与呼吸复合体成分的转录变化同时发生。我们进一步发现转录因子PGC - 1α和NRF - 1是线粒体复合体成分转录变化的原因。重要的是，用细胞因子白细胞介素 - 1β处理的HT22细胞导致PGC - 1α和NRF - 1类似程度的降低，从而导致呼吸复合体亚基的转录水平和蛋白质水平均降低。因此，用白细胞介素 - 1β处理的HT22细胞的呼吸功能受损。综上所述，我们证明呼吸复合体成分的减少以及随后的线粒体功能障碍是PND病理的一种新机制，为PND治疗提供了潜在的治疗靶点。
