Mechanism of action of synaptic mitochondrial damage in delayed cognitive recovery.

Delayed neurocognitive recovery following anesthesia and surgery is a common complication in older adult patients. Synapses are fundamental to cognitive function. The activity of synapses heavily depends on the energy supplied by synaptic mitochondria, which are significantly influenced by oxidative stress. Sirtuin 3 is a histone deacetylase located in the mitochondrial matrix that plays a pivotal role in regulating mitochondrial function. However, it remains unclear whether and how sirtuin 3 is involved in the development of delayed cognitive recovery. Therefore, in this study, we investigated the potential role of sirtuin 3 in synapses during delayed neurocognitive recovery. Our results showed that anesthesia and surgery induced cognitive impairment in mice and reduced sirtuin 3 protein expression. Overexpression of sirtuin 3 inhibited opening of the mitochondrial permeability transition pore by reducing acetylation of K166 on cyclophilin D and also rescued cognitive impairment. Aged mice carrying the cyclophilin D-K166R mutation exhibited significantly reduced cognitive impairment. Similarly, administering the mitochondrial permeability transition pore blocker, cyclosporine A, effectively alleviated the decline in synaptic mitochondrial function and cognitive impairment caused by anesthesia and surgery in aged mice. These results indicate that the sirtuin 3/cyclophilin D-K166/mPTP signaling pathway in hippocampal synaptic mitochondria is involved in delayed neurocognitive recovery of aged mice, suggesting this pathway could serve as a potential target for treatment.