Causes and Consequences of Mitochondrial Mutations

线粒体突变的原因和后果

基本信息

批准号：
10441596
负责人：
Justin C Havird
金额：
$ 39.51万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

项目摘要

PROJECT SUMMARY All complex eukaryotes rely on mitochondria to generate the cellular energy needed to maintain proper organismal function. Mutations in the mitochondrial genome underly multiple diseases and have been suggested to play a general role in aging. However, understanding the causes and consequences of mitochondrial mutations is limited by a focus on mammalian models. We will characterize mitochondrial mutations and their effects on physiology in diverse eukaryotic systems, including invertebrates, plants, and micro-eukaryotes. We will address three challenges that have hindered our understanding of mitochondrial mutations. First, we will use high-fidelity sequencing to characterize rates and types of mitochondrial mutations across eukaryotes and under different environments (e.g., increased oxidative stress), resulting in a “mitochondrial mutation atlas”. Of particular interest is the frequency of C -> T transitions resulting from replication errors vs. G -> T transversions characteristic of oxidative damage. The latter are implicated in aging theories, but the former have been shown to dominate the mutational landscape in mammalian mitochondrial genomes. Second, we will quantify distinct states of oxidative phosphorylation, reactive oxygen species (ROS) production, and metabolic rate in systems with varying sources and rates of mitochondrial mutations to determine how mutations affect organelle and organismal traits. We will also explore a mechanistic link between oxidative stress and mitochondrial mutations by increasing ROS via superoxide dismutase knockdown. Third, we will examine mitonuclear protein and transcript balance in two lineages where closely related organisms have disparate lifespans: rockfishes and cave salamanders. A shift towards reduced mitochondrial protein abundances has been identified as a conserved mechanism of longevity in long-lived strains of mice and nematodes, but it is unknown if natural long-lived populations have altered mitonuclear protein balance. We will also quantify mitochondrial mutations and physiology in these species to determine how natural selection may have shaped aging through mitochondrial processes. Overall, this research will provide a complement to previous work on mammalian models, which show uniformly high mitochondrial mutation rates. It will further uncover the possibilities for mitochondrial mutations to influence cellular and organismal processes, with implications for human health, disease progression, and aging.

项目概要所有复杂的真核生物都依赖线粒体来产生维持正常运转所需的细胞能量。线粒体基因组的突变是多种疾病的基础，并且已被证实。建议在衰老过程中发挥一般作用。但是，了解衰老的原因和后果。线粒体突变受到对哺乳动物模型的关注的限制。突变及其对不同真核系统生理学的影响，包括无脊椎动物、植物和我们将解决阻碍我们理解线粒体的三个挑战。首先，我们将使用高保真测序来表征线粒体的速率和类型。真核生物和不同环境下的突变（例如氧化应激增加），导致 “线粒体突变图谱”特别令人感兴趣的是 C -> T 转变的频率。复制错误与 G -> T 颠换是氧化损伤的特征，后者与衰老有关。理论，但前者已被证明主导哺乳动物线粒体的突变景观其次，我们将量化氧化磷酸化、活性氧（ROS）的不同状态。线粒体突变来源和速率不同的系统中的生产和代谢率确定突变如何影响细胞器和生物特征我们还将探索机制联系。通过超氧化物歧化酶增加 ROS 来研究氧化应激和线粒体突变之间的关系第三，我们将检查密切相关的两条线敲击中的线粒体核蛋白和转录本平衡。相关生物的寿命不同：石斑鱼和洞穴蝾螈的寿命正在减少。线粒体蛋白质丰度已被确定为长寿的保守机制小鼠和线虫品系，但尚不清楚自然长寿群体是否具有线粒体核我们还将量化这些物种的线粒体突变和生理学以确定总体而言，这项研究将揭示自然选择如何通过线粒体过程塑造衰老。为之前关于哺乳动物模型的工作提供了补充，这些模型显示出一致的高线粒体水平它将进一步揭示线粒体突变影响细胞和细胞的可能性。生物过程，对人类健康、疾病进展和衰老有影响。