Mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction in aged rats.
Mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction in aged rats.
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DOI：
10.18632/aging.103673
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发表时间：
2020-09-09
期刊：
影响因子：
--
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Chen Y;Zhang P;Lin X;Zhang H;Miao J;Zhou Y;Chen G
老年患者麻醉后常出现术后认知功能障碍（POCD），但其病理生理机制尚未完全阐明。据报道，七氟醚可抑制老年大鼠神经元的自噬；然而，线粒体自噬对于控制线粒体质量和神经元健康至关重要，在七氟烷诱导的老年大鼠 POCD 中的作用仍不清楚。因此，本研究探讨了线粒体自噬损伤是否与七氟醚诱发的认知功能障碍有关。我们发现七氟烷治疗抑制线粒体呼吸和线粒体自噬通量，在 H4 细胞和老年大鼠模型中观察到线粒体形态变化、溶酶体酸化受损、Tomm20 增加和 LAMP1 积累减少。雷帕霉素可以抵消七氟烷诱导的 ROS，恢复线粒体自噬并改善线粒体功能。此外，通过莫里斯水迷宫测试确定，雷帕霉素改善了接受七氟醚麻醉的老年大鼠所观察到的认知缺陷。这种改善与树突棘和锥体神经元数量的增加有关。 H4 细胞中 PARK2 的过表达（而非缺乏酶活性的突变型 PARK2）减少了 ROS 和 Tomm20 的积累，并逆转了七氟醚处理后的线粒体自噬功能障碍。这些发现表明线粒体自噬功能障碍可能是七氟烷诱导 POCD 的潜在机制，激活线粒体自噬可能为挽救认知缺陷提供新策略。
Postoperative cognitive dysfunction (POCD) is frequently observed in elderly patients following anesthesia, but its pathophysiological mechanisms have not been fully elucidated. Sevoflurane was reported to repress autophagy in aged rat neurons; however, the role of mitophagy, which is crucial for the control of mitochondrial quality and neuronal health, in sevoflurane-induced POCD in aged rats remains undetermined. Therefore, this study investigated whether mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction. We found sevoflurane treatment inhibited mitochondrial respiration and mitophagic flux, changes in mitochondria morphology, impaired lysosomal acidification, and increased Tomm20 and deceased LAMP1 accumulation were observed in H4 cell and aged rat models. Rapamycin counteracted ROS induced by sevoflurane, restored mitophagy and improved mitochondrial function. Furthermore, rapamycin ameliorated the cognitive deficits observed in aged rats given sevoflurane anesthesia as determined by the Morris water maze test; this improvement was associated with an increased number of dendritic spines and pyramidal neurons. Overexpression of PARK2, but not mutant PARK2 lacking enzyme activity, in H4 cells decreased ROS and Tomm20 accumulation and reversed mitophagy dysfunction after sevoflurane treatment. These findings suggest that mitophagy dysfunction could be a mechanism underlying sevoflurane-induced POCD and that activating mitophagy may provide a new strategy to rescue cognitive deficits.
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