STUB1-mediated PGC-1α ubiquitination promotes postoperative cognitive dysfunction in aged mice via modulating autophagylysosome machinery

Postoperative cognitive dysfunction (POCD) remains a prevalent neurological complication in elderly patients after anesthesia and surgery, with autophagy playing a crucial role. This study aimed to expound the molecular mechanisms underlying POCD. A POCD model in aged mice was established by internal fixation of tibial fracture under anesthesia. 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. Collectively, our findings uncover that STUB1-mediated PGC-1α ubiquitination contributes to POCD in aged mice through modulating TFEB-mediated autophagy-lysosome machinery, providing novel theoretical basis for the pathogenesis of POCD.