The role of clock control of DRP1 activity involved in postoperative cognitive dysfunction

Postoperative cognitive dysfunction (POCD) is a prevalent clinical issue following anesthesia and surgery. The onset of POCD, which is closely linked to circadian rhythm disturbance in previous studies, yet the underlying mechanism remains elusive. There is increasing evidence showed that mitochondrial architecture is coordinated by the circadian clock which DRP1 playing a crucial role. Nonetheless, how DRP1's mediation of mitochondrial dynamics influences POCD through circadian rhythm disruption is still unclear. To investigate this, mice were subjected to 6 h of 1.5 % isoflurane anesthesia from Zeitgeber Time ZT 14 to ZT20 to induce POCD. HT-22 cells underwent prolonged exposure to isoflurane in vitro. Cognitive function was assessed using the Y-maze and fear conditioning tests. Q-PCR and Western blot analyses were performed to measure relative protein expression. Mice's gross movement rhythms were continuously monitored using Mini-Mitter. Mitochondrial morphology was examined via Mito-Tracker imaging. ATP and ROS level were measured to evaluate mitochondrial function. Isoflurane anesthesia compromised the clock control of DRP1 activity in the hippocampus. This disruption of DRP1 phosphorylation rhythm impaired circadian ATP production, affected mitochondrial morphology and function, exacerbated circadian rhythm disturbances, and ultimately led to cognitive deficits in mice. Pretreatment with Mdivi-1, a specific DRP1 inhibitor, managed to reconstruct mitochondrial morphology and function, restore circadian ATP production and rhythm, thereby alleviating the cognitive impairment induced by isoflurane anesthesia. This study suggests that circadian DRP1 activity's regulation of mitochondrial energy metabolism in the hippocampus may play a significant role in the pathogenesis of POCD in mice.