Modes of Energy Production and clk-1 Life Extension

描述（由申请人提供）：线粒体氧化磷酸化是大多数真核生物产生能量的主要手段。完全去除这种能力通常会导致过早死亡。最近对秀丽隐杆线虫的研究令人惊讶，因为他们揭示了正常线粒体的许多关键成分的破坏！发电机械不会立即导致死亡，相反，它们通常会使成人寿命延长30%以上。理解为什么这些所谓的线粒体突变体寿命长是这个提议的基础。我们将验证这样一个假设，即Mit突变体之所以长寿，是因为它们残缺的线粒体在导致活性氧（ROS）输出减少的条件下得以维持和运作。秀丽隐杆线虫是一种天然的土壤生物。有时它被迫生活在低氧条件下。因此，它保留了几种不需要氧的途径来产生ATP和NAD(P)H。我们目前的数据表明，使用这种替代途径是一种策略，Mit突变体使用它来补充线粒体！能源赤字。在这项研究中，我们还将探索Mit突变体使用的替代能源生产途径。我们假设这些替代能量产生途径产生的产物直接与Mit突变体线粒体相互作用，影响其操作参数，包括ROS输出。秀丽隐杆线虫的进化史允许这个物种在有氧、低氧或无氧的情况下保留几种制造能量的途径。另一方面，人类只保留了其中的一些。尽管如此，我们相信这两个物种拥有相同的基本技术来潜在地降低线粒体！ROS生产。因此，研究Mit突变体可以让我们了解，为了延长寿命，线粒体必须设置什么样的新操作设置。可以想象，类似的设置可能也适用于我们自己的细胞。

DESCRIPTION (provided by applicant): Mitochondrial oxidative phosphorylation provides the major means of energy production in most eucaryotes. complete removal of this capacity often results in premature death. Recent studies using the nematode Caenorhabditis elegans are surprising because they have revealed that disruption of many of the key components of the normal mitochondria! energy-generating machinery do not result in immediate death, rather they typically result in greater than a 30% increase in adult lifespan. Understanding why these so called Mit (Mitochondrial) mutants are long-lived forms the basis of this proposal. We will test the hypothesis that the Mit mutants are long-lived because their crippled mitochondria are maintained and operated under] conditions that lead to a reduction in their reactive oxygen species (ROS) output. C. elegans is naturally a soil dwelling organism. There are times when it is forced to live under low oxygen conditions. As a consequence it has retained several non-oxygen requiring pathways for the generation of ATP and NAD(P)H. Our current data indicates that use of such alternate pathways is one strategy, that the Mit mutants use to supplement their mitochondria! energy deficit. In this study we will also explore the repertoire of alternate energy production pathways used by Mit mutants. We hypothesize that the products generated by these alternate energy production pathways directly interact with Mit mutant mitochondria to affect their operational parameters, including ROS output. The evolutionary history of C. elegans has permitted this species to retain several pathways for making energy in the presence or low or no oxygen. Humans, on the other hand, have retained only some of these. Nonetheless we believe both species have at their disposal the same basic techniques to potentially lower mitochondria! ROS production. Studying Mit mutants can therefore provide us with an understanding of what new operational settings mitochondria must be set at in order to gain life-span extension. It is conceivable that similar settings may also work for our own cells.