Excessive mitochondrial fission induces postoperative delirium in mice undergoing high-altitude deacclimatization by exacerbating neuroinflammation and synaptic injury

Postoperative delirium (POD) is a common complication after surgery. High-altitude deacclimatization (HADA), a physiological adaptation process, is associated with pathophysiological changes that may increase POD susceptibility. However, the underlying molecular mechanisms remain poorly understood. This study investigated the role of mitochondrial dynamics in POD pathogenesis in mice undergoing HADA and explored the neuroprotective effects of the mitochondrial fission inhibitor, Mdivi-1. C57BL/6 mice were subjected to simulated high-altitude exposure for 4 weeks, followed by anesthesia and surgery to induce a POD model. Mice undergoing HADA and surgery exhibited significant postoperative delirium-like behaviors. These behavioral deficits were accompanied by excessive mitochondrial fission, exacerbated neuroinflammation (evidenced by microglial and astrocyte activation), and synaptic injury within the hippocampus. Notably, pretreatment with Mdivi-1 effectively attenuated these pathological changes. It reduced mitochondrial fission, suppressed neuroinflammation, restored key synaptic proteins, and consequently, alleviated the postoperative delirium-like behaviors. In conclusion, this study suggests that excessive mitochondrial fission contributes to HADA-associated POD, potentially via exacerbating neuroinflammation and synaptic damage. Targeting mitochondrial fission presents a potential therapeutic strategy to prevent this serious postoperative complication.