Causes and Consequences of Mitochondrial Mutations

线粒体突变的原因和后果

• 批准号: 10275592
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10275592
• 关键词: Address; Affect; Aging; Atlases; Biological Models; Cell physiology; Characteristics; Complement; Complex; Disease; Disease Progression; Environment; Equilibrium; Eukaryota; Frequencies; Genome; Health; Human; Invertebrates; Link; Longevity; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Mouse Strains; Mutation; Natural Selections; Nematoda; Nuclear; Organelles; Organism; Oxidative Phosphorylation; Oxidative Stress; Physiological; Physiological Processes; Physiology; Plants; Play; Population; Process; Production; Property; Proteins; Reactive Oxygen Species; Replication Error; Research; Role; Salamander; Source; Superoxide Dismutase; System; Transcript; Work; disease-causing mutation; human disease; interest; knock-down; metabolic rate; mitochondrial genome; oxidative damage; theories; trait

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.

项目摘要 所有复杂的真核生物都依赖线粒体来产生维持正常细胞所需的能量。 有机体功能线粒体基因组中的突变是多种疾病的基础， 建议在衰老中发挥一般作用。然而，理解的原因和后果 线粒体突变受到关注哺乳动物模型的限制。我们将描述线粒体 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， 微型真核生物我们将解决阻碍我们理解线粒体的三个挑战， 突变。首先，我们将使用高保真测序来表征线粒体的速率和类型。 真核生物之间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跃迁的频率， 复制错误与氧化损伤特征的G -> T颠换。后者与衰老有关 理论，但前者已被证明是哺乳动物线粒体突变景观的主导 基因组其次，我们将量化氧化磷酸化、活性氧（ROS） 生产和代谢率在系统中具有不同的来源和速率的线粒体突变， 确定突变如何影响细胞器和生物体特征。我们还将探索一种机械的联系， 通过超氧化物歧化酶增加ROS，氧化应激和线粒体突变之间的关系 击倒。第三，我们将研究线粒体蛋白和转录平衡的两个谱系， 相关的生物有不同的寿命：岩鱼和洞穴蝾螈。向减少 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种群是否改变了线粒体 蛋白质平衡我们还将量化这些物种的线粒体突变和生理学，以确定 自然选择如何通过线粒体过程塑造衰老。总的来说，这项研究将 提供了一个补充，以前的工作对哺乳动物模型，其中显示一致高线粒体 突变率它将进一步揭示线粒体突变影响细胞和 有机体过程，对人类健康，疾病进展和衰老的影响。