Variability in mitochondrial genetics and functionality and its cell physiological effects

线粒体是细胞器，能产生细胞内生命所必需的能量。这种能量以三磷酸腺苷的形式产生，三磷酸腺苷是一种分子，在无数的细胞过程中用作能源。线粒体在确保生物体内充足的能量供应方面的重要性意味着，线粒体性能的可变性--以及随后它们产生ATP的能力的变化--可能会对生物体产生深远的影响。许多具有重大社会影响的疾病都与线粒体的蛋白质机制受损和线粒体功能下降有关，包括阿尔茨海默氏症、帕金森氏症和一系列遗传性疾病。生物体中线粒体系统的日益严重的损伤被认为是衰老的一个关键原因。此外，细胞线粒体含量的差异可能会影响基本的生物学行为，如干细胞如何分化为其他类型的细胞(当前干细胞研究中的一个关键问题)，以及肿瘤细胞对抗癌药物的反应。尽管线粒体的可变性在这些具有医学和生物学意义的情况下很重要，而且最近有大量实验数据表明线粒体在细胞内形成了一个丰富的物理系统，但几乎没有理论工作来提供对线粒体系统的定量了解。例如，由于缺乏对数量的了解，很难做出与临床相关的陈述，例如遗传线粒体疾病的可能性。该项目旨在通过建立线粒体可变性的几个关键原因和影响的数学和计算模型来解决这种不平衡问题。首先，将对线粒体基因组--编码产生ATP的蛋白质--以及蛋白质本身的损害进行定量研究，为帮助描述线粒体损害的概率和时间行为提供数学基础。其次，线粒体变异的这种和其他来源的影响--包括线粒体从亲代细胞到子代细胞的不均匀遗传--将被纳入一个群体细胞之间ATP水平差异的模型中。第三，通过将这些模型与数学生物学文献中现有的方法联系起来，将探索这种可变性对两个关键生物学现象的影响：干细胞的分化途径，以及肿瘤细胞对抗癌药物的反应。

Mitochondria are organelles that produce the energy that is necessary for life within our cells. This energy is produced in the form of ATP, a molecule that is used as an energy source in countless cellular processes. The importance of mitochondria in ensuring a sufficient energy supply within organisms means that variability in mitochondrial performance -- and subsequent changes in their capacity to produce ATP -- can have profound consequences for an organism. Many diseases with great societal impact are associated with damage to the protein machinery of mitochondria and subequent decrease in mitochondrial performance, including Alzheimer's, Parkinson's, and a host of inherited diseases. Increasing damage to the mitochondrial system in organisms is postulated to be a key cause of ageing. In addition, differences in the mitochondrial content of cells can affect fundamental biological behaviour, such as how stem cells differentiate into other cell types (a key question in current stem cell research) and how tumour cells respond to anti-cancer drugs. Despite the importance of mitochondrial variability in these situations of medical and biological interest, and a recent explosion of experimental data showing that mitochondria form a rich physical system within cells, there has been little theoretical work to provide a quantitative understanding of the mitochondrial system. This lack of quantitative understanding makes it very difficult, for example, to make statements of clinical relevance such as the probability of inheriting a mitochondrial disease. This project aims to address this imbalance by producing mathematical and computational models of several key causes and effects of mitochondrial variability. First, damage to the mitochondrial genome -- which encodes the proteins that are responsible for ATP production -- and to the proteins themselves will be explored quantitatively, providing a mathematical foundation to help describe probabilities and time behaviour of mitochondrial damage. Second, the effects of this and other sources of mitochondrial variability -- including uneven inheritance of mitochondria from a parent cell to a daughter cell -- will be incorporated into a model for the variation in ATP levels between cells in a population. Thirdly, the effects of this variability on two key biological phenomena: the differentiation pathways of stem cells, and the response of tumour cells to anti-cancer drugs, will be explored by linking these models with existing approaches in the mathematical biology literature.