Isoflurane Aggravates Pre-Existing Proteotoxicity in Adult Nematodes by Suppressing Mitochondrial Fitness

Post operative delirium (POD) is an acute complication characterized by fluctuating attention and confusion which may develop and persist into cognitive decline. POD is most commonly observed in elderly patients, particularly those with preexisting cognitive impairments. Isoflurane, as a widely used volatile anesthetic, is associated with POD. Utilizing the nematode C. elegans, we found that isoflurane enhances protein aggregation and long-lasting decline in protein homeostasis (proteostasis) of adult animals that express neurodegeneration-causing, abnormally long poly-glutamine stretches. Isoflurane-induced proteostasis impairments are dependent on the aging-regulating transcription factors DAF- 16/FOXO and SKN-1/NRF. We also show that reducing the activity of a certain components of the mitophagy mechanism and inducing mitochondrial biogenesis protect worms that exhibit weakened proteostasis, from isoflurane-induced proteotoxicity. Our observations provide novel insights into the mechanism that links isoflurane and POD, and highlight the potential of mitophagy modulators as alleviators of POD in elder patients with preexisting cognitive impairments.