N-acetyloxfenicine strongly induces mitohormesis in mice as well as in insects

Mitohormesis defines the increase in fitness induced by adaptive responses to mild mitochondrial stress. Here, we show that N-acetyloxfenicine (NAO) exerted higher thermotolerance than an endogenous mitohormesis inducer, N-acetyltyrosine (NAT). This activity was not observed in armyworm larvae injected with oxfenicine, suggesting the importance of N-acetylation. NAO-induced hormetic effect was triggered by transient perturbation of mitochondria, which causes a small increase in ROS production and leads to retrograde responses including enhanced expression of antioxidant enzyme genes via activation of FoxO transcription factors. Furthermore, pretreatment with NAO significantly repressed stress-induced peroxidation of lipids in mice and growth of colorectal cancer HCT116 cells that had been transplanted into nude mice. Taken together, NAO is a potent mitohormesis inducer that is similar to NAT in terms of structure and functions.

Automated summary

This study demonstrates that N-acetyloxfenicine (NAO) is a potent inducer of mitohormesis, exhibiting higher thermotolerance than the endogenous mitohormesis inducer, N-acetyltyrosine (NAT). NAO triggers hormetic effects through transient perturbation of mitochondria, leading to increased ROS production and enhanced expression of antioxidant enzyme genes via activation of FoxO transcription factors. Moreover, NAO pretreatment effectively suppresses lipid peroxidation in mice and inhibits the growth of colorectal cancer cells in nude mice.