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 线粒体是一种内共生细胞器， 编码少数蛋白质和核糖体和转运RNA，这些RNA是它们 功能协调发展的人类细胞拥有100- 1000个mtDNA，它们被积极地浓缩成 类核-蛋白质-DNA结构，是线粒体DNA遗传的细胞单位， 分布在动态线粒体“合胞体”内。尽管分子参与者 参与mtDNA复制和包装的基因已经被描述， 了解细胞水平上类核在哺乳动物体内的分布情况 细胞，以满足线粒体功能的需要，例如，他们是如何选择的， mtDNA复制以及mtDNA的细胞拷贝数是如何控制的。我们 发现在人类细胞中，参与mtDNA复制的类核在空间上是 与ER-线粒体接触位点的一小部分相连，这些位点注定用于线粒体 分裂和运动。我们发现线粒体DNA复制的连续事件， 线粒体分裂和线粒体运动在一个途径中共同起作用， 在细胞中优先分配新生的线粒体DNA，我们称之为ER连锁的线粒体DNA 传输在这项研究中，我们探索了这种ER相关的潜在机制。 通过解决细胞生物学和细胞行为来研究线粒体DNA传播途径 哺乳动物类核新的信息，在这个欠研究领域的细胞生物学将更多 准确揭示人类代谢性疾病的病因突变引起的， 线粒体DNA和影响线粒体DNA维持和衰老的核基因， 神经退行性疾病，这也与缺陷的mtDNA维护有关 以及线粒体和内质网功能障碍。