Mitophagy in perioperative neurocognitive disorder: mechanisms and therapeutic strategies

Abstract

Perioperative neurocognitive disorder (PND) is a common neurological complication after surgery/anesthesia in elderly patients that affect postoperative outcome and long-term quality of life, which increases the cost of family and social resources. The pathological mechanism of PND is complex and not fully understood, and the methods of prevention and treatment of PND are very limited, so it is particularly important to analyze the mechanism of PND. Research indicates that mitochondrial dysfunction is pivotal in the initiation and progression of PND, although the precise mechanisms remain elusive and could involve disrupted mitophagy. We reviewed recent studies on the link between mitophagy and PND, highlighting the role of key proteins in abnormal mitophagy and discussing therapeutic strategies aimed at mitophagy regulation. This provides insights into the mechanisms underlying PND and potential therapeutic targets.

Keywords: Mitophagy; NLRP3 inflammasome; Perioperative neurocognitive disorder; Pyroptosis.

Fig. 1

Physiological function of mitophagy in neurons. Under conditions such as hypoxia, nutrient deprivation, and cellular senescence, damaged mitochondria generate high levels of ROS, triggering mitophagy to clear these damaged mitochondria. Concurrently, mitophagy initiates caspase-family-induced apoptosis by removing damaged mitochondria, thus preventing excessive cytochrome C release due to mitochondrial injury. When mitophagy is impaired, the resulting ROS accumulation reduces ATP production and initiates programmed neuronal death. (This image was generated and provided under the BioRender license using BioRender. All rights and ownership of BioRender content belong to BioRender.)

Fig. 2

Molecular mechanism by which mitophagy regulates PND. A Surgery/anesthesia elevates ROS levels in the hippocampus, activates NLRP3 inflammasomes, stimulates the release of pro-inflammatory cytokines, intensifies neuroinflammatory responses, and contributes to the development of PND. Activation of the NLRP3 inflammasome induces mitochondrial damage, mtDNA buildup, and mtROS production, while inhibiting mitophagy by promoting caspase-1-dependent Parkin cleavage. B Surgery/anesthesia can inhibit mitophagy and promote the production of PND by promoting the production of proteins such as Aβ, tau and TNFAIP1. (This image was generated and provided under the BioRender license using BioRender. All rights and ownership of BioRender content belong to BioRender.)