OBJECTIVE: Postoperative cognitive dysfunction (POCD) is a common neurological complication in elderly patients after anesthesia and surgery, and autophagy plays a critical regulatory role in its pathogenesis. This study aimed to systematically clarify the molecular mechanism by which STUB1 mediates POCD in aged mice.
METHODS: A POCD model in aged mice was established by internal fixation of tibial fracture under anesthesia. Cognitive function was evaluated via conditioned fear test and Morris water maze, and neuronal damage and apoptosis was evaluated through H&E and TUNEL staining. To identify molecular mechanisms, RNA-seq was conducted on the hippocampus, and STUB1/PGC-1α/TFEB axis was identified. STUB1 was knocked out and overexpressed in mouse hippocampal neuron cells (HT22), respectively. The expression of STUB1/PGC-1α/TFEB axis, and the activity of downstream mitophagy, autophagy-lysosome, and apoptosis were investigated both in the hippocampus and neuron cells through qRT-PCR, immunofluorescence, western blot, transmission electron microscope, flow cytometry, and TUNEL staining. PGC-1α ubiquitination was measured through Co-IP.
RESULTS: Following surgery and anesthesia, the aged mice showed cognitive dysfunction, and neuronal apoptosis, with elevated expression of E3 ubiquitin ligase STUB1, decreased PGC-1α and TFEB expression, and increased PGC-1α ubiquitination in the hippocampus. Moreover, aberrant PINK1/PARKIN-mediated mitophagy, and LAMP-1/LC3/Cathepsin D autophagy-lysosome signaling were found in the hippocampus. In neuron cells, STUB1 overexpression reduced the expression of PGC-1α and TFEB, enhanced PGC-1α ubiquitination, facilitated neuron cell apoptosis, and attenuated mitophagy and autophagy-lysosome pathways.
CONCLUSION: STUB1 directly binds to PGC-1α and promotes its ubiquitination and degradation, thereby inhibiting the TFEB-dependent autophagy-lysosome pathway and inducing hippocampal neuronal apoptosis, ultimately contributing to POCD in aged mice. This study provides a novel theoretical basis for understanding the pathogenesis of POCD and identifies potential therapeutic targets.
