PDF(Pubmed)
Abstract：
During maturation oocytes undergo a recently discovered mitochondrial proteome remodeling event in flies1, frogs1, and humans2. This oocyte mitochondrial remodeling, which includes substantial changes in electron transport chain (ETC) subunit abundance1,2, is regulated by maternal insulin signaling1. Why oocytes undergo mitochondrial remodeling is unknown, with some speculating that it might be an evolutionarily conserved mechanism to protect oocytes from genotoxic damage by reactive oxygen species (ROS)2. In Caenorhabditis elegans, we previously found that maternal exposure to osmotic stress drives a 50-fold increase in offspring survival in response to future osmotic stress3. Like mitochondrial remodeling, we found that this intergenerational adaptation is also regulated by insulin signaling to oocytes3. Here, we used proteomics and genetic manipulations to show that insulin signaling to oocytes regulates offspring\'s ability to adapt to future stress via a mechanism that depends on ETC composition in maternal oocytes. Specifically, we found that maternally expressed mutant alleles of nduf-7 (complex I subunit) or isp-1 (complex III subunit) altered offspring\'s response to osmotic stress at hatching independently of offspring genotype. Furthermore, we found that expressing wild-type isp-1 in germ cells (oocytes) was sufficient to restore offspring\'s normal response to osmotic stress. Chemical mutagenesis screens revealed that maternal ETC composition regulates offspring\'s response to stress by altering AMP kinase function in offspring which in turn regulates both ATP and glycerol metabolism in response to continued osmotic stress. To our knowledge, these data are the first to show that proper oocyte ETC composition is required to link a mother\'s environment to adaptive changes in offspring metabolism. The data also raise the possibility that the reason diverse animals exhibit insulin regulated remodeling of oocyte mitochondria is to tailor offspring metabolism to best match the environment of their mother.
摘要：
在成熟过程中，卵母细胞在果蝇中经历了最近发现的线粒体蛋白质组重塑事件1，青蛙1,人类2。这种卵母细胞线粒体重塑，其中包括电子传递链（ETC）亚基丰度的实质性变化1,2，受母体胰岛素信号1调节。为什么卵母细胞经历线粒体重塑是未知的，有人推测，保护卵母细胞免受活性氧（ROS）2的遗传毒性损伤可能是一种进化上保守的机制。在秀丽隐杆线虫中,我们之前发现，母体暴露于渗透应激会导致后代存活率增加50倍，以应对未来的渗透应激3。像线粒体重塑一样，我们发现，这种代际适应也受到胰岛素信号对卵母细胞3的调节。这里,我们使用蛋白质组学和基因操作表明，通过依赖于母体卵母细胞中ETC组成的机制，向卵母细胞传递胰岛素信号调节后代适应未来应激的能力。具体来说,我们发现，母本表达的nduf-7（复杂的I亚基）或isp-1（复杂的III亚基）突变等位基因改变了后代在孵化时对渗透胁迫的反应，而与后代基因型无关。此外，我们发现，在生殖细胞（卵母细胞）中表达野生型44isp-1足以恢复后代对渗透胁迫的正常反应。化学诱变筛选显示，母体ETC成分通过改变后代的AMP激酶功能来调节后代对应激反应，进而调节ATP和甘油代谢以响应持续的渗透胁迫。据我们所知,这些数据首次表明，需要适当的卵母细胞ETC组成，才能将母亲的环境与后代代谢的适应性变化联系起来。数据还提出了一种可能性，即不同动物表现出胰岛素调节的卵母细胞线粒体重塑的原因是为了调整后代代谢以最佳地匹配其母亲的环境。
