Variability in mitochondrial genetics and functionality and its cell physiological effects

线粒体遗传学和功能的变异性及其细胞生理效应

• 批准号: MR/J013617/1
• 负责人: Iain Johnston
• 金额: $ 30.34万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ013617%2F1
• 关键词: Variability; mitochondrial; genetics; functionality; its

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.

线粒体是一种细胞器，它产生细胞内生命所必需的能量。这种能量以ATP的形式产生，ATP是一种在无数细胞过程中用作能量来源的分子。线粒体在确保生物体内足够的能量供应方面的重要性意味着线粒体性能的变化-以及随后产生ATP能力的变化-可能对生物体产生深远的影响。许多具有巨大社会影响的疾病与线粒体蛋白质机制的损伤和线粒体性能的随后降低有关，包括阿尔茨海默氏症、帕金森氏症和许多遗传性疾病。据推测，生物体中线粒体系统的日益受损是衰老的一个关键原因。此外，细胞线粒体含量的差异可以影响基本的生物学行为，例如干细胞如何分化为其他细胞类型（当前干细胞研究的关键问题）以及肿瘤细胞如何对抗癌药物作出反应。尽管线粒体变异性在这些情况下的医学和生物学利益的重要性，以及最近爆炸的实验数据表明，线粒体形成一个丰富的物理系统内的细胞，一直很少有理论工作，以提供一个定量的线粒体系统的理解。这种定量理解的缺乏使得它非常困难，例如，作出临床相关性的陈述，如遗传线粒体疾病的概率。该项目旨在通过产生线粒体变异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。首先，线粒体基因组（编码负责ATP产生的蛋白质）和蛋白质本身的损伤将被定量研究，为描述线粒体损伤的概率和时间行为提供数学基础。其次，这种和其他线粒体变异性来源的影响-包括线粒体从亲本细胞到子细胞的不均匀遗传-将被纳入群体细胞之间ATP水平变化的模型中。第三，这种变异性对两个关键的生物现象的影响：干细胞的分化途径，以及肿瘤细胞对抗癌药物的反应，将通过将这些模型与数学生物学文献中的现有方法联系起来来探讨。

项目成果

MtDNA segregation in heteroplasmic tissues is common in vivo and modulated by haplotype differences and developmental stage.

• DOI: 10.1016/j.celrep.2014.05.020
• 发表时间: 2014-06-26
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Burgstaller JP;Johnston IG;Jones NS;Albrechtová J;Kolbe T;Vogl C;Futschik A;Mayrhofer C;Klein D;Sabitzer S;Blattner M;Gülly C;Poulton J;Rülicke T;Piálek J;Steinborn R;Brem G
• 通讯作者: Brem G

Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations.

• DOI: 10.1038/s41467-018-04797-2
• 发表时间: 2018-06-27
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Burgstaller JP;Kolbe T;Havlicek V;Hembach S;Poulton J;Piálek J;Steinborn R;Rülicke T;Brem G;Jones NS;Johnston IG
• 通讯作者: Johnston IG

Closed-form stochastic solutions for non-equilibrium dynamics and inheritance of cellular components over many cell divisions.

• DOI: 10.1098/rspa.2015.0050
• 发表时间: 2015-08-08
• 期刊: Proceedings. Mathematical, physical, and engineering sciences
• 作者: Johnston IG;Jones NS
• 通讯作者: Jones NS

A tractable genotype-phenotype map modelling the self-assembly of protein quaternary structure.

• DOI: 10.1098/rsif.2014.0249
• 发表时间: 2014-06-06
• 期刊: Journal of the Royal Society, Interface
• 作者: Greenbury SF;Johnston IG;Louis AA;Ahnert SE
• 通讯作者: Ahnert SE

What is the function of mitochondrial networks? A theoretical assessment of hypotheses and proposal for future research.

• DOI: 10.1002/bies.201400188
• 发表时间: 2015-06
• 期刊: BioEssays : news and reviews in molecular, cellular and developmental biology
• 作者: Hoitzing H;Johnston IG;Jones NS
• 通讯作者: Jones NS