Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats.
Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats.
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DOI：
10.1111/cns.14261
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发表时间：
2023-11
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
新出现的证据表明，线粒体功能障碍在术后神经认知恢复延迟（dNCR）的发病机制中发挥着至关重要的作用。线粒体存在于一个动态平衡中，涉及分裂和融合以调节形态，并通过线粒体自噬去除受损的线粒体来维持正常的细胞功能。尽管如此，线粒体形态和线粒体自噬之间的关系，以及它们如何影响线粒体功能的发展，术后dNCR，仍然知之甚少。在这里，我们观察了海马神经元线粒体和线粒体自噬活性的形态学改变，并评估了它们在老年大鼠全身麻醉和手术应激后在dNCR中的相互作用。首先，我们评估了老年大鼠麻醉/手术后的空间学习记忆能力。检测海马线粒体功能和线粒体形态。随后，Mdivi‐1和siDrp 1分别在体内和体外抑制线粒体分裂。然后我们检测了线粒体自噬和线粒体功能。最后，我们用雷帕霉素激活线粒体自噬，观察线粒体形态和功能。手术损害了海马依赖性空间学习和记忆能力，并导致线粒体功能障碍。它还增加海马神经元线粒体分裂和抑制线粒体自噬。Mdivi‐1通过抑制线粒体分裂改善老年大鼠的线粒体自噬和学习记忆能力。通过siDrp 1敲除Drp 1也改善了线粒体自噬和线粒体功能。同时，雷帕霉素抑制线粒体过度分裂，改善线粒体功能。手术同时增加线粒体分裂和抑制线粒体自噬活性。从机制上讲，线粒体分裂/融合和线粒体自噬活性相互作用，并且都参与了术后dNCR。手术应激后的这些线粒体事件可能为术后dNCR的治疗干预提供新的靶点和方式。术后dNCR中线粒体分裂和线粒体自噬的相互作用。剖腹手术增加了Drp 1诱导的线粒体分裂，抑制了老年海马中的线粒体自噬，从而导致线粒体功能障碍和术后dNCR。线粒体超分裂和线粒体自噬抑制共存并相互作用，有望成为术后dNCR的潜在干预靶点。
Emerging evidence suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of postoperative delayed neurocognitive recovery (dNCR). Mitochondria exist in a dynamic equilibrium that involves fission and fusion to regulate morphology and maintains normal cell function via the removal of damaged mitochondria through mitophagy. Nonetheless, the relationship between mitochondrial morphology and mitophagy, and how they influence mitochondrial function in the development of postoperative dNCR, remains poorly understood. Here, we observed morphological alterations of mitochondria and mitophagy activity in hippocampal neurons and assessed the involvement of their interaction in dNCR following general anesthesia and surgical stress in aged rats. Firstly, we evaluated the spatial learning and memory ability of the aged rats after anesthesia/surgery. Hippocampal mitochondrial function and mitochondrial morphology were detected. Afterwards, mitochondrial fission was inhibited by Mdivi‐1 and siDrp1 in vivo and in vitro separately. We then detected mitophagy and mitochondrial function. Finally, we used rapamycin to activate mitophagy and observed mitochondrial morphology and mitochondrial function. Surgery impaired hippocampal‐dependent spatial learning and memory ability and caused mitochondrial dysfunction. It also increased mitochondrial fission and inhibited mitophagy in hippocampal neurons. Mdivi‐1 improved mitophagy and learning and memory ability of aged rats by inhibiting mitochondrial fission. Knocking down Drp1 by siDrp1 also improved mitophagy and mitochondrial function. Meanwhile, rapamycin inhibited excessive mitochondrial fission and improved mitochondrial function. Surgery simultaneously increases mitochondrial fission and inhibits mitophagy activity. Mechanistically, mitochondrial fission/fusion and mitophagy activity interact reciprocally with each other and are both involved in postoperative dNCR. These mitochondrial events after surgical stress may provide novel targets and modalities for therapeutic intervention in postoperative dNCR. Mitochondrial fission and mitophagy reciprocal interactions in postoperative dNCR. Laparotomy increases Drp1‐induced mitochondria fission and inhibits mitophagy in the aged hippocampus, thus causing mitochondrial dysfunction and postoperative dNCR. Mitochondrial hyperfission and mitophagy inhibition coexist and interact with each other, which is expected to become a potential intervention target for dNCR after surgery.
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DOI：
10.1083/jcb.202205104
发表时间：
2022-10-03
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