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.

摘要 为了充分了解人类衰老的基本生物学基础，并准确地确定潜在治疗的时间， 旨在预防与年龄有关的病理学，确定何时发生 人的衰老会发生沉淀。导致人类衰老的过程之一是线粒体突变。 随着年龄的增长，线粒体DNA（mtDNA）突变不断积累，从而加速了自然衰老 过程，并有助于各种与年龄有关的疾病，包括癌症，肌肉萎缩， 神经变性然而，由于细胞中线粒体基因组的多样性， 突变最初是无害的。线粒体DNA突变需要克隆扩展才能引起疾病。因为这 扩展过程需要时间，我们假设，突变，沉淀年龄相关的病理出现 线粒体衰老的速度早在病理学变得明显之前就已经确定了。 我们建议用一种新的DNA聚合酶γ（PolgA）小鼠模型来验证这一假设， 复制线粒体基因组。该模型表达了DNA聚合酶的易错版本 可以随意用WT等位基因替换的γ。因此，我们可以关闭线粒体突变， 在动物的生命周期中的任何时候，并确定生命早期发生的突变如何影响以后的病理学 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 细胞测序和双链体测序来追踪这些突变在我们小鼠寿命中的命运。 这些实验将描述各种组织中每一种可能的mtDNA突变的自然历史， 有效地剖析控制mtDNA突变对人类健康影响的参数。最后我们 建议通过操纵线粒体融合和线粒体自噬来恢复体细胞和衰老小鼠的活力， 试图从有害的线粒体DNA突变中治愈它们。如果成功，这一战略可能会提供一个潜在的 治疗多种儿科mtDNA疾病，以及年龄相关的线粒体成分 疾病因此，我们的实验有可能彻底改变我们对这种关系的理解 线粒体突变和衰老之间的关系，并提供强大的新工具，以打击遗传和 与mtDNA突变相关的年龄相关疾病。