Transgenerational inheritance of increased mtDNA triggers mitochondrial UPR and modulates aging [WT vs. TGQ]

It would be evolutionarily beneficial if the information of transient stresses experienced by parents could be passed on to descendants as a forecast of the challenges to come. Here, we discovered that neuronal mitochondrial perturbations can transmit the mitochondrial unfolded protein response (UPRmt) to offspring for multiple generations in Caenorhabditis elegans. The transgenerational induction of UPRmt was caused by a higher level of maternally inherited mitochondrial DNA (mtDNA), which disturbed the balance of oxidative phosphorylation subunits encoded by mtDNA and nuclear DNA. Furthermore, an increase in mtDNA levels requires Wnt/b-catenin signaling to propagate across generations, thereby inducing the UPRmt and conferring increased lifespan and stress tolerance. Thus, transgenerational increase in mtDNA levels and the UPRmt enable offspring to live longer and confer stress tolerance.