Temporal control of mitochondrial mutagenesis

线粒体诱变的时间控制

• 批准号: 10587905
• 负责人: Marc Vermulst
• 金额: $ 50.72万
• 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/10587905
• 关键词: Address; Affect; Age; Age-Months; Aging; Alleles; Animals; Autophagocytosis; Biology; Brain; Cell Aging; Cells; Childhood; Complement; DNA biosynthesis; DNA polymerase gamma; Development; Disease; Enzymes; Event; Genetic; Genome; Health; Heart; Human; Induced Mutation; Inherited; Intestines; Lead; 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; 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础生物学，并准确地确定潜在的治疗时间 旨在预防与年龄相关的病理学，因此确定这些事件何时发生至关重要 促使人体发生衰老。驱动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，从而加速自然衰老 过程并导致各种与年龄相关的疾病，包括癌症、肌肉萎缩和 神经变性。然而，由于细胞中线粒体基因组的多样性，从头线粒体DNA 突变最初是无害的。 MtDNA 突变需要克隆扩展才能引起疾病。因为这个 扩张过程需要时间，我们假设会出现导致年龄相关病理的突变 线粒体衰老的速度早在病理变得明显之前就已确定。 我们建议用 DNA 聚合酶 γ (PolgA) 的新小鼠模型来检验这一假设。 复制线粒体基因组。该模型表达了 DNA 聚合酶的易错版本 gamma 可以随意替换为 WT 等位基因。因此，我们可以关闭线粒体诱变 动物一生中的任何时间，并确定生命早期发生的突变如何影响以后的病理学 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、单突变检测 细胞测序和双工测序来追踪这些突变在小鼠一生中的命运。 这些实验将描述各种组织中每种可能的 mtDNA 突变的自然历史， 有效剖析控制 mtDNA 突变对人类健康影响的参数。最后，我们 提出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， 尝试治愈他们免受有害的线粒体DNA突变的影响。如果成功，该策略可以提供潜在的 治疗多种儿童线粒体DNA疾病，以及与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来对抗遗传和衰老 与 mtDNA 突变相关的年龄相关疾病。