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, a widely used volatile anesthetic, is associated with POD. However. how exposure to isoflurane affects the integrity of the proteome is largely obscure. Utilizing the nematode C. elegans, we found that isoflurane leads to a 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, and can be alleviated by the knockdown of certain components of the mitophagy mechanism. Accordingly, induction of mitochondrial biogenesis protects worms that are challenged by protein aggregation from isoflurane-induced proteotoxicity. Our observations provide novel insights into the mechanism that links isoflurane, proteotoxicity and POD, and highlight the potential of mitophagy modulators as alleviators of POD.