Mild mitochondrial impairment enhances innate immunity and longevity through ATFS-1 and p38 signaling

While mitochondrial function is essential for life in all multicellular organisms, a mild impairment of mitochondrial function can extend longevity in model organisms. By understanding the molecular mechanisms involved, these pathways might be targeted to promote healthy aging. In studying two long-lived mitochondrial mutants in C. elegans, we found that disrupting subunits of the mitochondrial electron transport chain results in upregulation of genes involved in innate immunity, which is driven by the mitochondrial unfolded protein response (mitoUPR) but also dependent on the canonical p38-mediated innate immune signaling pathway. Both of these pathways are required for the increased resistance to bacterial pathogens and extended longevity of the long-lived mitochondrial mutants, as is the FOXO transcription factor DAF-16. This work demonstrates that both the p38-mediated innate immune signaling pathway and the mitoUPR act in concert on the same innate immunity genes to promote pathogen resistance and longevity, and that input from the mitochondria can extend longevity by signaling through these pathways. This indicates that multiple evolutionarily conserved genetic pathways controlling innate immunity also function to modulate lifespan.

尽管线粒体功能对所有多细胞生物的生存至关重要，轻度的线粒体功能损伤却可延长模式生物的寿命。若能阐明其中涉及的分子机制，便可靶向调控这些通路以促进健康衰老。本研究针对秀丽隐杆线虫（C. elegans）的两种长寿线粒体突变体展开分析，结果发现，破坏线粒体电子传递链的亚基会导致先天免疫相关基因的上调，这一过程由线粒体未折叠蛋白反应（mitoUPR）介导，同时依赖于经典p38介导的先天免疫信号通路。上述两条通路与FOXO转录因子DAF-16一样，均为该长寿线粒体突变体增强细菌病原体抗性、延长寿命所必需。本研究证实，p38介导的先天免疫信号通路与线粒体未折叠蛋白反应可协同作用于同一批先天免疫相关基因，从而提升病原体抗性并延长寿命；同时，线粒体可通过上述通路传递信号，进而延长生物体寿命。这表明，多种调控先天免疫的进化保守遗传通路，同时也可参与调节生物体的寿命。