Targeting Mitochondria for Postoperative Cognitive Dysfunction: From Mechanisms to Therapeutics

Postoperative cognitive dysfunction (POCD) is a frequent neurological complication in older surgical patients, leading to substantial declines in quality of life and placing a considerable burden on society. This review provides a comprehensive overview of how mitochondrial dysfunction contributes to POCD, including disrupted energy metabolism, excessive reactive oxygen species production, calcium imbalance, and abnormalities in mitochondrial dynamics and quality control processes. These mitochondrial impairments further trigger neuroinflammation and activate multiple cell death pathways. In addition, the review examines current mitochondria-targeted therapeutic strategies and their underlying mechanisms, highlighting the neuroprotective roles of agents such as SS-31, Mdivi-1, P110, and NLRP3 inhibitors in preclinical studies. It also explores the promise of multi-target combinational treatments, time-specific interventions, and individualized therapeutic approaches. Finally, the review discusses key barriers to clinical translation such as limited blood–brain barrier permeability, unintended drug effects, and altered pharmacokinetics in the elderly and considers emerging technologies, including nanocarrier drug-delivery systems and AI-guided personalized treatment plans, as potential tools for achieving more precise prevention and management of POCD.