Transgenerational inheritance of mitochondrial hormetic oxidative stress mediated by histone H3K4me3 and H3K27me3 modifications

Mitochondrial hormetic oxidative stress (mtHOS) is crucial in physiology and disease; however, its effects on epigenetic inheritance and organism fitness across generations remains elusive. Utilizing the C. elegans as a model, we elucidate that parental exposure to mtHOS not only elicits a lifespan extension in the exposed individuals but also confers this longevity advantage to the progeny through the transgenerational epigenetic inheritance (TEI) mechanism. This transgenerational transmission of lifespan prolongation depends on the activation of the UPRmt and the synergistic action of the transcription factors DAF-16/FOXO and SKN-1/Nrf2. Additionally, the H3K4me3 and H3K27me3 serve as epigenetic mediators, selectively marking and regulating the expression of genes associated with oxidative stress response and longevity determination. Our findings illuminate the mechanisms underlying the implementation and transmission of mtHOS, revealing a sophisticated interplay among oxidative stress response genes and chromatin remodeling that collectively enhances the progeny's adaptive resilience to future challenges.