The Memory of Neuronal Mitochondrial Stress is Inherited Transgenerationally via Elevated Mitochondrial DNA Levels

Qian Zhang, Zihao Wang, Wenfeng Zhang, Qingbo Wen, Xinyu Li, Jun Zhou, Xueying Wu, Yongqing Guo, Yangli Liu, Changshuo Wei, Wenfeng Qian, Ye Tian

Nature Cell Biology


The memory of stresses experienced by parents can be passed on to descendants as a forecast of the challenges to come. Here, we discovered that the neuronal mitochondrial perturbation-induced systemic mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans can be transmitted to offspring over multiple generations. The transgenerational activation of UPRmt is mediated by maternal inheritance of elevated levels of mitochondrial DNA (mtDNA), which causes the proteostasis stress within mitochondria. In addition, results from intercrossing studies using wild C. elegans strains further support that maternal inheritance of higher levels of mtDNA can induce the UPRmt in descendants. The mitokine Wnt signaling pathway is required for the transmission of elevated mtDNA levels across generations, thereby conferring lifespan extension and stress resistance to offspring. Collectively, our results reveal that the nervous system can transmit stress signals across generations via increasing mtDNA in the germline, allowing descendants to better cope with anticipated challenges.