Cellular basis of mtDNA transmission.

项目总结 线粒体是具有残留基因组(Mtdna)的内共生细胞器。 编码少数蛋白质和核糖体以及转运RNA，这些RNA对其 功能。人类细胞拥有100-1000个线粒体DNA，活跃地浓缩成 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。尽管分子玩家 涉及线粒体DNA的复制和包装已经被描述，更少的是 了解在细胞水平上类核物质如何在哺乳动物体内分布 细胞以满足线粒体功能的需要，例如，它们是如何被选择用于 线粒体DNA复制以及如何控制线粒体DNA的细胞拷贝数。我们 发现在人类细胞中，参与线粒体DNA复制的类核在空间上是 连接到一小部分内质网-线粒体接触位点，定位于线粒体 分裂和能动性。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共同发挥作用的途径是 优先在细胞中分布新生的线粒体DNA，我们称之为内质网连接的线粒体DNA 变速箱。在这项资助中，我们探索了这种内质网关联的潜在机制 线粒体DNA传递途径通过解决细胞生物学和行为的 哺乳动物的类核。在这一未被充分研究的细胞生物学领域，新的信息将会更多 准确揭示由基因突变引起的人类代谢性疾病的病因 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，也与线粒体DNA维护缺陷有关 线粒体和内质网功能障碍。

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.