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

线粒体是一种小的双膜结合细胞器，在所有真核细胞中都有很高的拷贝数。线粒体是细胞能量代谢的主要组成部分，在细胞内发生氧化磷酸化(OXPHOS)；它们还参与钙离子流量调节、细胞凋亡调节和细胞内信号转导。线粒体包含数百个拷贝的自身小的环状基因组，这些基因组对于细胞器的功能是不可或缺的，并编码大量的RNA分子以及OXPHOS电子传输链机制的几个蛋白质成分。线粒体基因组的变化与衰老和癌症等疾病状态有关。在人类中，线粒体基因组大约有16.5kb长，通常在其他相同的副本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损伤后，以及在癌症中，一些这种低水平的变异会增强。我们推测，观察到的低水平序列变异可能与线粒体DNA损伤和修复之间正在进行的平衡有关，并可能表明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可变性，以确定其原因和对细胞功能的影响。对这一现象的更好理解将为我们提供对基本线粒体生物学、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逆行信号来源的重要性的见解。BBSRC的研究重点领域是数据驱动生物学、整个生命过程中的健康衰老，探索新的工作方式

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