Mechanistic Investigation of TSPO-Mediated Dysregulation of Mitochondrial Copper Homeostasis in Microglia and its Role in Perioperative Neurocognitive Disorders

Perioperative neurocognitive disorders (PND) are common complications in elderly surgical patients; their mechanisms remain unclear and no effective therapeutic targets exist. This study aims to determine whether copper dyshomeostasis contributes to PND via 18 kDa translocator protein (TSPO)-mediated pathways and to evaluate the therapeutic potential of a TSPO inhibitor. An aged-mouse model of PND was established by right carotid exposure, and BV-2 microglia were stimulated with lipopolysaccharide (LPS) to mimic neuroinflammation. Copper ions, TSPO expression, and mitochondrial function were assessed in the hippocampus, serum, and cultured cells. Postoperative mice exhibited elevated copper levels in both the hippocampus and serum, accompanied by a significant increase in hippocampal TSPO expression. In vitro, LPS-induced TSPO over-expression in BV-2 cells led to copper accumulation and mitochondrial dysfunction, both of which were reversed by the TSPO inhibitor PK11195. TSPO-mediated disruption of copper homeostasis is a critical mechanism in PND, and targeting TSPO offers a novel strategy for PND prevention and treatment.