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

• Published in: FEBS letters Vol. 597; no. 2; pp. 288 - 297
• Main Authors: Matsumura, Takashi, Ono, Masaya, Osada, Satoshi, Matsuhisa, Fumikazu, Ochiai, Masanori, Hayakawa, Yoichi
• Format: Journal Article
• Language: English
• Published: England 01.01.2023
• Subjects: Animals; Antioxidants - metabolism; FoxO; Insecta - metabolism; Keap1; Mice; Mice, Nude; mitochondria; Mitochondria - metabolism; mitohormesis; N‐acetyl‐l‐oxfenicine; N‐acetyl‐l‐tyrosine; Reactive Oxygen Species - metabolism; Signal Transduction; Keap1; FoxO; N-acetyl-l-tyrosine; mitohormesis; mitochondria; N-acetyl-l-oxfenicine
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.14566

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. N‐acetyloxfenicine (NAO) increases thermotolerance of insects. The NAO‐induced hormetic effect was triggered by transient perturbation of mitochondria, which causes a small increase in ROS production and leads to retrograde responses: NAO treatment enhanced the expression of antioxidant enzyme genes via activation of FoxO. Therefore, NAO is a potent mitohormesis inducer that shares close similarity with N‐acetyltyrosine in terms of structure and biological functions.