Maintaining Mitochondrial Health into Old Age

摘要/摘要 背景和相关性：线粒体是所有人类细胞的重要组成部分。在超过 50种遗传性新陈代谢疾病，最使人衰弱的疾病扰乱线粒体电子传递 链(等)，结果是细胞有效地制造能量的能力。条件，如MELAS， LHON、MNGIE、NARP和MERRF均起源于线粒体缺陷。仅在美国，每年就有1 每4,000名儿童出生时，他们将在10岁之前患上线粒体疾病。 随着疾病的发展，越来越清楚的是线粒体ETC功能缺陷也与 更常与老年有关的疾病。这些疾病包括心脏病、II型糖尿病、帕金森氏症 疾病、阿尔茨海默氏症和癌症。目前有15%的美国人患有这些慢性疾病 退化性疾病。虽然还不能说线粒体导致了这些问题，但很明显 线粒体的变化也参与其中，因为它们的功能发生了明显的变化。毫无疑问，有一个 需要了解在所有年龄段中维持线粒体功能的过程。 研究目的：对抗与年龄相关的线粒体功能下降的一种方法是采取 反对线粒体电子传递链功能障碍的保守细胞机制的优势 功能障碍。这种机制被称为逆行反应，因为功能失调的线粒体 能够向细胞核发送信号来协调适应性反应。由此可以得出结论 逆行反应可能被选择性地激活，以努力恢复线粒体网络的活力。我们 发现了一种新的线粒体逆行反应，可以延长线虫C. 优雅女装。我们的主要研究目标是机械地定义线粒体功能障碍是如何触发这种情况的 新的逆行反应途径，它如何起到延长生命的作用，以及这种信息如何被翻译 对人类来说。为了快速而严谨地完成这些研究，我们将采用最先进的技术 包括LC-ESI-MS/MS、CRISPR/Cas9 DNA编辑、RNA-Seq、共聚焦显微镜等 技巧。 预期结果和影响：到这项研究完成时，我们预计将定义一条关键途径 在线虫中被激活以响应线粒体电子传输链功能障碍，不仅起作用 以对抗线粒体功能障碍，但补偿到延长寿命的程度。我们也期待着 已经确定了这种途径可能在多大程度上可以翻译给哺乳动物。通过学习如何 利用延缓线粒体功能障碍的机制，我们的研究将对衰老产生重大影响。 这是因为线粒体功能障碍，无论是因果的还是后果性的，都是每个主要的 西方社会的老年性疾病。

Abstract/Summary Background and Relevance: Mitochondria form an essential component of all human cells. Of the more than 50 inherited diseases of metabolism, the most debilitating ones disrupt the mitochondrial electron transport chain (ETC), and as a consequence the ability of cells to make energy efficiently. Conditions such as MELAS, LHON, MNGIE, NARP and MERRF all have their origin in mitochondrial defects. Each year in the US alone, 1 in 4,000 children are born who will develop a mitochondrial disease before age 10. On top of these tragic disease, it has become increasingly clear that defects in mitochondrial ETC function are also linked with diseases more commonly associated with old age. These include heart disease, Type II diabetes, Parkinson's Disease, Alzheimer's dementia, and cancer. 15% of the US population currently suffer from these chronic degenerative disorders. While it cannot yet be said that mitochondria cause these problems it is clear that changes in mitochondria are involved, because their function is measurably altered. Unquestionably, there is a need to understand processes that maintain mitochondrial functionality throughout all ages. Study Objectives: One approach to countering age-related decline in mitochondrial function is to take advantage of conserved cellular mechanisms that oppose mitochondrial electron transport chain dysfunction dysfunction. Such mechanisms have been termed retrograde responses, because dysfunctional mitochondria are capable of sending a signal to the cell's nucleus to orchestrate adaptive responses. It follows that retrograde responses might be selectively activated in an effort to rejuvenate the mitochondrial network. We have discovered a novel mitochondrial retrograde response that can extend lifespan in the nematode C. elegans. Our primary study objectives are to mechanistically define how mitochondrial dysfunction triggers this novel retrograde response pathway, how it functions to extend life, and how this information can be translated to humans. To accomplish these studies quickly and rigorously we will employ state-of the art techniques including LC-ESI-MS/MS, CRISPR/Cas9 DNA editing, RNA-Seq, confocal microscopy, among other techniques. Expected Results and Impact: By the completion of this study we expect to have defined how a key pathway that is activated in C. elegans in response to mitochondrial electron transport chain dysfunction, works not only to counteract mitochondrial dysfunction, but to compensate to the point of increasing life span. We also expect to have determined the extent to which this pathway might be translatable to mammals. By learning how to harness mechanisms that delay mitochondrial dysfunction, our studies stand to have a major impact on aging. This is because mitochondrial dysfunction, whether causative or consequential, is a feature of every major age-related disease of western society.