Cellular basis of mtDNA transmission.

mtDNA 传输的细胞基础。

• 批准号: 9426983
• 负责人: Jodi M. Nunnari
• 金额: $ 30.22万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9426983
• 关键词: ATP Synthesis Pathway; Address; Affect; Aging; Area; Behavior; Biochemical; Biological Assay; Cells; Cellular Assay; Cellular Structures; Cellular biology; DNA; DNA Structure; DNA Topoisomerases; Dynein ATPase; Etiology; Event; Family; Functional disorder; Genes; Genome; Giant Cells; Grant; Guanosine Triphosphate Phosphohydrolases; Human; Interphase Cell; Kinesin; Link; Maintenance; Mammalian Cell; Mediating; Metabolic Diseases; Microtubules; Mitochondria; Mitochondrial DNA; Mitochondrial Inheritance; Molecular; Movement; Neurodegenerative Disorders; Nuclear; Organelles; Outer Mitochondrial Membrane; Oxidative Phosphorylation; Pathway interactions; Population; Positioning Attribute; Process; Proteins; Proteome; Proteomics; Recruitment Activity; Regulation; Replication Initiation; Residual state; Resolution; Ribosomal RNA; Role; Set protein; Site; Structure; Surface; TOP3A gene; Testing; Transact; Transfer RNA; base; cell behavior; cell motility; comparative; disease-causing mutation; helicase; in vitro Assay; live cell imaging; mitochondrial dysfunction; novel; receptor; rho; segregation; transmission process; yeast two hybrid system

PROJECT SUMMARY Mitochondria are endosymbiotic organelles that possess a residual genome (mtDNA) encoding a handful of proteins and ribosomal and transfer RNAs essential for their functions. Human cells possess 100-1000s of mtDNAs, actively condensed into nucleoids - protein-DNA structures that are the cellular unit of mtDNA inheritance – distributed within dynamic mitochondria “syncytia”. Although the molecular players involved in mtDNA replication and packaging have been described, much less is understood about how at the cellular level nucleoids are distributed within mammalian cells to meet the needs for mitochondrial function, for example, how they are selected for mtDNA replication and how the cellular copy number of mtDNA is controlled. We discovered that in human cells, nucleoids engaged in mtDNA replication are spatially linked to a small subset of ER-mitochondria contact sites destined for mitochondrial division and motility. We found that the successive events of mtDNA replication, mitochondrial division and mitochondrial motility function together in a pathway that preferentially distributes nascent mtDNA in cells, which we term ER-linked mtDNA transmission. In this grant, we explore the underlying mechanisms of this ER-linked mtDNA transmission pathway by addressing the cell biology and behavior of the mammalian nucleoid. New information in this understudied area of cell biology will more accurately reveal the etiology of human metabolic diseases caused by mutations in mtDNA and in nuclear genes that affect mtDNA maintenance and in aging and neurodegenerative disorders, which are also linked to defective mtDNA maintenance and mitochondrial and ER dysfunction.

项目摘要 线粒体是具有残留基因组（mtDNA）的内体组织细胞器 编码少数蛋白质和核糖体和转移RNA对其 功能。人类细胞具有100-1000 s的mtdnas，积极凝结成 核苷 - 蛋白-DNA结构，是mtDNA遗传的细胞单位 - 分布在动态线粒体“合成”中。虽然分子玩家 已经描述了参与mtDNA复制和包装，更不用说了 了解在哺乳动物中如何分布细胞水平的核苷 细胞满足线粒体功能的需求，例如，如何选择它们 mtDNA复制以及如何控制mtDNA的细胞拷贝数。我们 发现在人类细胞中，参与mtDNA复制的核苷在空间上是 链接到一小部分ER-Monochontria接触站点，该接触位点注定为线粒体 分裂和运动。我们发现MTDNA复制的成功事件， 线粒体分裂和线粒体运动函数在一条途径中一起 优先在细胞中分布新生的mtDNA，我们将其称为ER连接mtDNA 传播。在这笔赠款中，我们探索了这种ER链接的基本机制 MTDNA传播途径通过解决细胞生物学和行为 哺乳动物核苷。在这个知识的细胞生物学领域中的新信息将更多 准确地揭示了由突变引起的人类代谢疾病的病因 mtDNA和影响mtDNA维持以及衰老和核基因的核基因 神经退行性疾病也与缺陷的mtDNA维持有关 线粒体和ER功能障碍。