Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats

• Published in: CNS neuroscience & therapeutics 2023-11, Vol.29 (11), p.3322-3338
• Main Authors: Li, Yitong, Li, Yue, Chen, Lei, Li, Yi, Liu, Kaixi, Hong, Jingshu, Wang, Qian, Kang, Ning, Song, Yanan, Mi, Xinning, Yuan, Yi, Han, Dengyang, Liu, Taotao, Yang, Ning, Guo, Xiangyang, Li, Zhengqian
• Format: Article
• Language: English
• Subjects: Anesthesia; Animals; Cognition; Cognitive ability; Cytology; Dynamins; Geriatrics; Hippocampus; Homeostasis; Iodine; Laboratory animals; Laparotomy; Memory; Mitochondria; Mitochondrial DNA; Mitochondrial Dynamics; Mitophagy; Mitophagy - physiology; Morphology; Original; Pathogens; Proteins; Rapamycin; Rats; Sirolimus; Spatial discrimination learning; Spatial memory; Surgery
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.14261

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.