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.