Role of Mitochondrial DNA Mutations in Aging in Neuronal Cells

线粒体 DNA 突变在神经细胞衰老中的作用

• 批准号: 7191724
• 负责人: Yidong Bai
• 金额: $ 28.98万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7191724
• 关键词: Age; Aging; Aging-Related Process; Apoptosis; Applications Grants; Biochemical; Biogenesis; Brain; Brain region; Cell Culture System; Cell Line; Cell model; Cell physiology; Cells; DNA; Electron Transport; Energy Supply; Evaluation; Exhibits; Frequencies; Functional disorder; Generations; Genes; Genetic; Genetic Transcription; Goals; Individual; Lipids; Measures; Methods; Mitochondria; Mitochondrial DNA; Molecular; Molecular Genetics; Monitor; Mus; Mutation; Nerve Endings; Neuroblastoma; Neurons; Nuclear; Oxidative Phosphorylation; Oxidative Stress; Phenotype; Physiological; Proteins; Reactive Oxygen Species; Regulation; Relative (related person); Reporting; Respiration; Role; Sequence Analysis; Signal Transduction; Synaptosomes; System; Techniques; Technology; Testing; Time; Tissues; Translations; age group; age related; established cell line; human tissue; improved; insight; middle age; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial genome; mutant; programs; respiratory; theories

DESCRIPTION (provided by applicant): Our long-term goal is to study the role of mitochondria in aging. The overall goal of this grant application is to test the mitochondria! theory of aging and, in particular, to investigate the role of mitochondrial DNA (mtDNA) mutations in mouse brain during aging. As one of the most favored hypotheses, the mitochondrial theory of aging, predicts that somatic mitochondria DNA (mtDNA) mutations accumulate with time, and the compromised mitochondrial function resulting from these mutations is then responsible for various aging phenotypes. However, there has been no comprehensive study of the overall accumulation of mtDNA mutations during aging, and the physiological consequences of aging-related mtDNA mutations are largely unclear. We recently established a method to transfer mtDNA from mouse nerve endings, i.e., synaptosomes to a cell system, and we have improved methods to isolate and characterize mtDNA mutations. Combined with established mitochondrial molecular genetic and biochemical technologies, we can, for the first time, investigate the accumulation of mtDNA mutations in neuronal cells during aging by evaluating individual mtDNA from the synaptosomes. The particular hypothesis to be tested in this proposal is that mutations in the mitochondrial genome accumulate during aging in mouse neuronal cells; these mtDNA mutations in turn compromise mitochondrial function and may result in oxidative damage to various cellular components including mtDNA in neuronal cells. We will perform genetic and functional analyses of aging-related mtDNA mutations by transferring synaptosomal mtDNA to a cell line system. This will reveal low frequency mtDNA mutations that could not be identified by other methods. By generating neuronal cell models that carry aging-related mtDNA mutations, we will also characterize the physiological consequences of the mutations, in particular those related to oxidative damage. The successful completion of this project will not only help to test the mitochondrial theory of aging, but could also provide insights into the underlying mechanisms of the aging process.

描述（由申请人提供）：我们的长期目标是研究线粒体在衰老中的作用。该赠款应用程序的总体目标是测试线粒体！衰老理论，尤其是研究小鼠大脑在衰老过程中线粒体DNA（mtDNA）突变的作用。作为最受欢迎的假设之一，衰老的线粒体理论预测，体细分线粒体DNA（mtDNA）突变会随着时间的推移积累，而这些突变引起的损害的线粒体功能则负责各种衰变表型。然而，尚无对衰老过程中mtDNA突变的总体积累的全面研究，与衰老相关的mtDNA突变的生理后果在很大程度上不清楚。我们最近建立了一种从小鼠神经端（即突触体）转移mtDNA的方法，并具有改进的分离和表征mtDNA突变的方法。结合已建立的线粒体分子遗传和生化技术，我们可以首次通过评估突触体中的单个mtDNA来研究衰老过程中神经元细胞中mtDNA突变的积累。该提议中要检验的特定假设是，小鼠神经元细胞衰老过程中线粒体基因组的突变积累。这些mtDNA突变反过来损害了线粒体功能，并可能导致对包括神经元细胞中包括mtDNA在内的各种细胞成分的氧化损伤。我们将通过将突触体mtDNA转移到细胞系系统中对与衰老相关的mtDNA突变进行遗传和功能分析。这将揭示低频mtDNA突变，而其他方法无法识别。通过产生带有与衰老相关的mtDNA突变的神经元细胞模型，我们还将表征突变的生理后果，尤其是与氧化损伤有关的突变。该项目的成功完成不仅将有助于测试衰老的线粒体理论，而且还可以提供对衰老过程的基本机制的见解。