Investigation of the mitochondrial DNA heteroplasmy in the context of DNA damage and repair - WCUB, BfH, ENWW

DNA 损伤和修复背景下线粒体 DNA 异质性的研究 - WCUB、BfH、ENWW

• 批准号: 1810150
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1810150
• 关键词: Investigation; mitochondrial; DNA; heteroplasmy; context

Mitochondria are small double--membrane bound organelles found at high copy numbers within all eukaryotic cells. Mitochondria are the main component of the cell energy metabolism where oxidative phosphorylation (OXPHOS) takes place within cells; they are also involved in calcium ion flux regulation, apoptosis regulation, and intracellular signalling. Mitochondria contain hundreds of copies of their own small circular genomes that are indispensable to the organelle function and that encode numerous RNA molecules as well as several protein components of the OXPHOS electron transport chain machinery. Mitochondrial genome changes are associated with aging and disease states such as cancer. In humans, the mitochondrial genome is roughly 16.5kb long and normally shows a low level sequence variation between otherwise identical copies, known as heteroplasmy. Upon certain types of DNA damage, as well as in cancers, some of this low-level variation becomes enhanced. We speculate that the low-level sequence variation observed may be linked with an on-going balance between mitochondrial DNA damage and repair, and may be indicative of the baseline activity of the different repair mechanisms taking place in the mitochondria. Therefore we aim to investigate this low-level sequence variability to determine its causes and effects on cell function. A better understanding of this phenomenon will provide us with insights into fundamental mitochondrial biology, mitochondrial DNA repair mechanisms, and the importance of the mitochondria as the sources of retrograde signalling within cells via small peptides and other signal carriers.BBSRC research priority areas Data driven biology, healthy ageing across the lifecourse, exploiting new ways of working

线粒体是一种小的双膜结合细胞器，在所有真核细胞中以高拷贝数存在。线粒体是细胞能量代谢的主要组成部分，其中氧化磷酸化（OXPHOS）在细胞内发生;它们还参与钙离子通量调节、凋亡调节和细胞内信号传导。线粒体含有数百个其自身的小型环状基因组的拷贝，所述基因组对于细胞器功能是不可或缺的，并且编码许多RNA分子以及OXPHOS电子传递链机制的几种蛋白质组分。线粒体基因组变化与衰老和疾病状态如癌症有关。在人类中，线粒体基因组大约16.5kb长，通常在其他相同的拷贝之间显示出低水平的序列变异，称为异质性。在某些类型的DNA损伤以及癌症中，这种低水平的变异中的一些变得增强。我们推测观察到的低水平序列变异可能与线粒体DNA损伤和修复之间的持续平衡有关，并且可能指示线粒体中发生的不同修复机制的基线活性。因此，我们的目标是研究这种低水平的序列变异性，以确定其原因和对细胞功能的影响。更好地理解这一现象将为我们提供基本的线粒体生物学，线粒体DNA修复机制，以及线粒体作为细胞内通过小肽和其他信号载体的逆行信号来源的重要性的见解。BBSRC研究优先领域数据驱动生物学，整个生命过程中的健康老龄化，探索新的工作方式