Hippocampus-Based Mitochondrial Respiratory Function Decline Is Responsible for Perioperative Neurocognitive Disorders

Abstract

Perioperative neurocognitive disorders (PNDs) are a type of cognitive dysfunction occurring with a higher incidence in elderly patients. However, the pathological mechanism of PND and effective treatment remain elusive. We generated a PND mouse model by providing wild-type mice with surgical trauma; in our case, we used tibial fracture to investigate PND pathology. Mice aged 7–8 months were randomly divided into two groups: the surgery (tibial fracture) group and the control (sham) group. All mice were subjected to anesthesia. We examined the transcriptome-wide response in the hippocampus, a brain region that is tightly associated with memory formation, of control mice and mice subjected to surgical trauma at day 1 and day 3 after the surgical procedure. We observed reduced transcript levels of respiratory complex components as early as day 1 after surgery, and subsequent protein changes were found at day 3 after surgical trauma. Consequently, the activities of respiratory complexes were reduced, and adenosine triphosphate (ATP) production was decreased in the hippocampus of mice with surgical operations, supporting that respiratory chain function was impaired. In support of these conclusions, the mitochondrial membrane potential (MMP) levels were decreased, and the reactive oxygen species (ROS) levels were significantly increased. Mechanistically, we demonstrated that surgery induced a significant increase in cytokine IL-1β levels at day 1 after surgery, which concomitantly occurred with transcript changes in respiratory complex components. We further uncovered that transcription factors PGC-1α and NRF-1 were responsible for the observed transcript changes in mitochondrial complex components. Importantly, HT22 cells treated with the cytokine IL-1β resulted in similar reductions in PGC-1α and NRF-1, leading to a reduction of both the transcript and protein levels of respiratory complex subunits. Consequently, respiratory function was impaired in HT22 cells treated with IL-1β. Taken together, we demonstrated that reductions in respiratory complex components and subsequent impairment in mitochondrial functions serve as a novel mechanism for PND pathology, providing a potential therapeutic target for PND treatment.

Transcranial near-infrared laser improves postoperative neurocognitive disorder in aged mice via SIRT3/AMPK/Nrf2 pathway

“…The postoperative neurocognitive disorder is a common CNS complication in patients after anesthesia/surgery, especially in aged people, which causes a negative effect on personality, social ability, and cognitive function ( Evered et al, 2018 ; Liu J. et al, 2021 ). Increasing evidence showed that neuroinflammation, oxidative stress damage, and synaptic dysfunction could be responsible for PND ( Zhao et al, 2019 ; He et al, 2022 ). Consequently, alleviating these mechanisms may provide a potential method for the treatment of PND.…”

Dexmedetomidine attenuates postoperative spatial memory impairment after surgery by reducing cytochrome C

“…Mitochondria are the main provider of energy for neurons, and as such, neurons have high vulnerability to death or injury caused by mitochondrial dysfunction. Mitochondrial dysfunction has been increasingly recognized as an essential contributor to PND [ 5 ]. Mitochondrial fragmentation during dysfunction is related to mitochondrial osmotic swelling, collapse of the mitochondrial membrane potential (Δ Ψm ) and dysfunction of the electron transport chain [ 6 ].…”