The memory of neuronal mitochondrial stress is inherited transgenerationally via elevated mitochondrial DNA levels

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. Furthermore, 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 signalling 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
by increasing mtDNA in the germline, enabling descendants to better cope with anticipated challenges.

父母所经历的压力记忆可传递给子代，以此预判后代即将面临的挑战。本研究发现，秀丽隐杆线虫（Caenorhabditis elegans）中由神经元线粒体扰动引发的全身性线粒体未折叠蛋白反应（mitochondrial unfolded protein response, UPRmt），可跨多代传递给子代。UPRmt的跨代激活由母系遗传获得的高水平线粒体DNA（mitochondrial DNA, mtDNA）所介导，该过程会引发线粒体内部的蛋白质稳态应激。此外，利用野生型秀丽隐杆线虫菌株进行的互交实验结果进一步证实，母系遗传获得的高水平mtDNA可诱导后代产生UPRmt。线粒体信号因子Wnt信号通路（mitokine Wnt signalling pathway）是跨代传递高水平mtDNA所必需的，该通路可使子代获得寿命延长与应激抵抗能力。综上，本研究结果表明，神经系统可通过增加生殖细胞中的mtDNA含量跨代传递应激信号，使后代能够更好地应对预期中的挑战。