Temporal control of mitochondrial mutagenesis

线粒体诱变的时间控制

• 批准号: 10709005
• 负责人: Marc Vermulst
• 金额: $ 51.96万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709005
• 关键词: Acceleration; Address; Affect; Age; Age Months; Aging; Alleles; Animals; Autophagocytosis; Biology; Brain; Cell Aging; Cells; Childhood; Clonal Expansion; Complement; DNA biosynthesis; DNA polymerase gamma; Development; Disease; Enzymes; Event; Genetic; Genome; Health; Heart; Human; Induced Mutation; Inherited; Intestines; Life; Liver; Longevity; Malignant Neoplasms; Mammalian Cell; Mediating; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Motion; Mus; Muscular Atrophy; Mutagenesis; Mutation; Mutation Detection; Natural History; Nerve Degeneration; Pathogenicity; Pathology; Predisposition; Premature aging syndrome; Process; Production; Rejuvenation; Risk Factors; Skeletal Muscle; Societies; Somatic Cell; Testing; Time; Tissues; age related; combat; detection method; driving force; experimental study; insight; mitochondrial DNA mutation; mitochondrial genome; mouse model; novel; prevent; single cell sequencing; therapy development; tool

ABSTRACT To fully understand the basic biology that underlies human aging, and accurately time potential treatments that are aimed at preventing age-related pathology, it will be of vital importance to determine when the events that precipitate human aging occur. One of the processes that drives human aging is mitochondrial mutagenesis. Mitochondrial DNA (mtDNA) mutations accumulate as we grow older, which accelerates the natural aging process and contributes to various age-related diseases, including cancer, muscle wasting and neurodegeneration. However, due to the multiplicity of mitochondrial genomes in a cell, de novo mtDNA mutations are initially harmless. MtDNA mutations need to clonally expand to cause disease. Because this expansion process takes time, we hypothesize that the mutations that precipitate age-related pathology arise relatively early in life, and that the pace of mitochondrial aging is set long before pathology becomes apparent. We propose to test this hypothesis with a new mouse model of DNA polymerase gamma (PolgA), the enzyme that replicates the mitochondrial genome. This model expresses an error prone version of DNA polymerase gamma that can be replaced with a WT allele at will. Accordingly, we can turn off mitochondrial mutagenesis at any time during the animal’s lifespan and determine how mutations that occur early in life affect pathology later in life. In addition, we will use various mutation detection techniques, including random mutation capture, single cell sequencing and duplex sequencing to track the fate of these mutations over the lifespan of our mice. These experiments will describe the natural history of every possible mtDNA mutation in various tissues, effectively dissecting the parameters that control the impact of mtDNA mutations on human health. Finally, we propose to rejuvenate somatic cells and aging mice by manipulating mitochondrial fusion and mitophagy, in an attempt to cure them from deleterious mtDNA mutations. If successful, this strategy could provide a potential treatment for multiple pediatric mtDNA diseases, as well as the mitochondrial component of age-related diseases. Accordingly, our experiments have the potential to revolutionize our understanding of the relationship between mitochondrial mutagenesis and aging, and provide powerful new tools to combat both inherited and age-related diseases that are associated with mtDNA mutations.

抽象的 充分了解人类衰老的基本生物学，以及准确的时间潜在治疗 旨在防止与年龄相关的病理学，确定何时发生的事件至关重要 沉淀人老化发生。驱动人衰老的过程之一是线粒体诱变。 随着年龄的增长，线粒体DNA（mtDNA）突变会累积，这加速了自然衰老 过程并导致各种与年龄有关的疾病，包括癌症，肌肉浪费和 神经变性。但是，由于细胞中的线粒体基因组的多样性，从头mtDNA 突变最初是无害的。 mtDNA突变需要克隆地扩展以引起疾病。因为这个 扩展过程需要时间，我们假设出现了与年龄相关的病理学的突变 在生命的早期，与线粒体衰老的速度相关，早在病理显而易见之前就开始了。 我们建议使用新的DNA聚合酶伽马（Polga）的新小鼠模型（酶）检验该假设。 这复制了线粒体基因组。该模型表达了易于DNA聚合酶的误差版本 可以随意用WT等位基因代替的伽马。根据，我们可以关闭线粒体诱变 动物寿命中的任何时候，确定生命早期发生的突变如何影响病理 在生活中。此外，我们将使用各种突变检测技术，包括随机突变捕获，单个 细胞测序和双链测序，以跟踪小鼠寿命中这些突变的命运。 这些实验将描述各个时机中所有可能的mtDNA突变的自然历史， 有效解剖控制mtDNA突变对人类健康的影响的参数。最后，我们 通过操纵线粒体融合和线粒体来恢复体细胞和老化小鼠的建议 尝试从有害mtDNA突变中治愈它们。如果成功，该策略可能会提供潜力 多种小儿MTDNA疾病以及与年龄相关的线粒体成分的治疗 疾病。彼此之间，我们的实验有可能彻底改变我们对关系的理解 在线粒体诱变和衰老之间，并提供强大的新工具来打击遗传和 与MTDNA突变相关的年龄相关疾病。