Mitochondrial Genetics of Aging in Drosophila

项目摘要 衰老的主要原因被认为是线粒体中产生的活性氧物种(ROS)。 作为氧化磷酸化(OXPHOS)的副产物。要么增加RO的操纵 清除或减少ROS的产生在一些系统中延长了寿命，但不是所有系统。 卡路里或饮食限制(CR或DR)仍然是最可重复的干预措施 延长所有被研究的生物体的寿命。最近的研究已经确定了一种关系 在CR或DR之间，改变了线粒体功能，延长了寿命。在这份提案中，我们 提供清楚的证据表明线粒体DNA单倍型1)可以延长或缩短寿命，2)修改 饮食限制的延寿作用，3)改变胰岛素的延寿作用 受体底物突变chico1。这些发现提供了核线粒体DNA的原理证据 上位性作图是揭示饮食延寿遗传机制的有效方法 限制。这一结果导致了一种假设，即线粒体DNA中编码的基因对 依赖营养的延年益寿。我们将开发这些线粒体DNA替代菌株 要使用Rpd3-Sir2和TOR通路的上位性实验来验证这一假设 在以营养为基础的长寿变化中发挥重要作用。这些基因结构也将被用于 为了检验mtDNA基因通过改变基因改变寿命这一普遍假设 氧化损伤的程度。有三个具体的目标将检验这些假设： 1)mtDNA基因型是否改变了依赖Rpd3的寿命延长？我们将测试 线粒体基因修饰RPD3延年益寿的假说，以及RPD3的S 独立于博士2)mtDNA基因是否改变了饮食对Sir2的依赖效应 限制？我们将检验这一假设，即mtDNA基因改变Sir2在 通过将mtDNA与过度表达和组织特异性配对来调节对DR的反应 不同饮食中的表达结构。3)mtDNA基因是否改变了TOR途径 对营养感知和延年益寿的影响？我们将检验线粒体DNA的假设 通过将mtDNA与TSC2配对，基因改变TOR和TSC2在延长寿命中所起的作用 这些基因的亚型和组织特异性表达结构。

Project Summary A primary cause of aging is thought to be reactive oxygen species (ROS) produced in mitochondria as byproducts of oxidative phosphorylation (OXPHOS). Manipulations that either increase ROS scavenging or decrease ROS production have extended longevity in some, but not all systems. Caloric or dietary restriction (CR or DR) remains the single most repeatable intervention that extends longevity in all organisms studied to date. Recent studies have identified a relationship between CR or DR, altered mitochondrial function, and extended longevity. In this proposal we present clear evidence that mtDNA haplotypes 1) can extend or shorten longevity, 2) modify the longevity-extending effects of diet restriction, 3) modify the longevity-extending effects of the insulin receptor substrate mutation chico1. These findings provide proof of principle that nuclear-mtDNA epistasis mapping is effective in uncovering genetic mechanisms of longevity extension by diet restriction. The results lead to the hypothesis that genes encoded in mtDNA are critical for the nutrient-dependent modification of longevity. We will exploit these mtDNA replacement strains to test this hypothesis using epistasis experiments with the Rpd3 - Sir2 and TOR pathways that play important roles in nutrient-based changes in longevity. These genetic constructs will also be used to test the general hypothesis that mtDNA genotype modifies longevity through changes in the level of oxidative damage. There are three specific aims that will test each of these hypotheses: 1) Does mtDNA genotype alter the Rpd3-dependent extension of longevity? We will test the hypothesis that mitochondrial genes modify the effect of Rpd3 on longevity, and Rpd3's independence from DR. 2) Does mtDNA genotype alter the Sir2-dependent effects of dietary restriction? We will test the hypothesis that mtDNA genotype modifies the role Sir2 plays in regulating the response to DR by pairing mtDNAs with over-expression and tissue specific expression constructs on different diets. 3) Does mtDNA genotype modify the TOR pathway effects on nutrient sensing and longevity extension? We will test the hypothesis that mtDNA genotype modifies the role that TOR and Tsc2 play in extending longevity by pairing mtDNAs with hypomorphic and tissue specific expression constructs of these genes.