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The Flux Capacitor: How mitochondria modulate metabolic flux and gene expression

通量电容器：线粒体如何调节代谢通量和基因表达

基本信息

批准号：
BB/S003681/1
负责人：
Nick Lane
金额：
$ 118.6万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS003681%2F1
关键词：
Flux Capacitor How mitochondria modulate

项目摘要

Mitochondria are often called the powerhouses of the cell as they produce nearly all the energy needed for living. Recent research shows that mitochondria do much more than generate energy: they integrate virtually all metabolic inputs and outputs of cells. These inputs and outputs depend on diet, temperature, growth, age and physical demands. If mitochondria cannot match metabolic supply to demand, they signal a stress state to the nucleus resulting in changes in the activity of genes. These changes might ameliorate the stress, or if that fails, tip the cell towards programmed death. Mitochondria can be seen as 'flux capacitors'.The problem is that mitochondria are uniquely vulnerable to mechanical faults. This is because the vital proteins that carry out respiration are encoded by two different genomes that have a tendency to diverge - genes in the mitochondria mutate nearly 50 times faster than those in the nucleus, and are inherited from the mother only, whereas genes in the nucleus are recombined by sex every generation. These radical differences in inheritance can result in mismatches that affect the performance of mitochondria - the flux capacitor itself becomes faulty, which impacts on both the inputs and outputs of the cell, and its stress state. Mutations in either the mitochondrial or nuclear genes encoding the proteins involved in respiration can cause catastrophic diseases, and more subtle genetic differences contribute to common conditions such as diabetes, cancer, neurodegeneration and ageing. But the extent to which mismatches between mitochondrial and nuclear genes affect health through the lifecourse is uncertain, as there are hundreds of mitochondria in every cell, and their performance can differ substantially. Animal models show that 'mitonuclear mismatches' really do affect health, for example causing male infertility and altered lifespan. Even when the health effects are too subtle to notice, mitonuclear mismatches can alter the activity of thousands of genes. Because these mismatches are produced every generation, they most likely have substantial health impacts. Until recently, though, this has been nearly impossible to verify. Our programme of research will analyse how mitonuclear mismatches affect the inputs and outputs of mitochondria, and how these changes impact on gene activity and health. We will use a model organism, the fruitfly Drosophila, in which mitochondrial genes have been deliberately mismatched to the nuclear genome. These flies have known health outcomes such as male infertility, but how their faulty mitochondria cause these defects is unknown; treatments that might improve their health are unknown for the same reasons. We will address these questions using cutting-edge experimental methods. Specifically, we will measure mitochondrial performance in real time to establish how mitonuclear mismatches alter the function of different tissues over the lifecourse of males and females, and how mitochondrial performance is altered by dietary treatments. We will generate global profiles of metabolite levels, allowing us to relate mitochondrial function to the 'metabolomic profile' of each tissue. Finally, we will use Next Generation Sequencing to measure changes in gene activity in each tissue, with each treatment, in males and females. We will use this information to build a set of mathematical models that map changes in mitochondrial function to shifts in metabolic flux, gene activity and health, allowing us to generalise our conclusions to be valuable for human and animal health.Our pilot studies show that we can indeed measure real-time changes in mitochondrial performance linked with male infertility. Antioxidant treatments have remarkably different outcomes depending on mitonuclear mismatches, in one case improving male fertility yet causing high (90%) mortality in female flies. We therefore anticipate our findings will have important implications for lifelong health.

线粒体通常被称为细胞的发电站，因为它们产生几乎所有生活所需的能量。最近的研究表明，线粒体不仅仅是产生能量：它们整合了细胞几乎所有的代谢输入和输出。这些投入和产出取决于饮食、温度、生长、年龄和身体需求。如果线粒体不能使代谢的供给与需求相匹配，它们就会向细胞核发出压力状态的信号，从而导致基因活性的变化。这些变化可能会减轻压力，或者如果失败，则会使细胞走向程序性死亡。线粒体可以被看作是“通量电容器”，问题是线粒体特别容易受到机械故障的影响。这是因为进行呼吸的重要蛋白质是由两个不同的基因组编码的，这两个基因组有分化的趋势-线粒体中的基因突变的速度比细胞核中的基因快近50倍，并且只从母亲那里遗传，而细胞核中的基因每一代都会通过性别重组。这些遗传上的根本差异可能导致影响线粒体性能的失配-通量电容器本身出现故障，这会影响细胞的输入和输出及其压力状态。编码参与呼吸的蛋白质的线粒体或核基因的突变可能导致灾难性的疾病，更微妙的遗传差异会导致糖尿病，癌症，神经退行性疾病和衰老等常见疾病。但是，线粒体和核基因之间的不匹配在多大程度上影响整个生命过程中的健康是不确定的，因为每个细胞中有数百个线粒体，它们的表现可能有很大差异。动物模型表明，“线粒体不匹配”确实会影响健康，例如导致男性不育和寿命改变。即使对健康的影响太细微而不易察觉，线粒体的错配也会改变数千个基因的活性。由于这些不匹配每一代都会产生，它们很可能会对健康产生重大影响。然而，直到最近，这几乎是不可能核实的。我们的研究计划将分析线粒体错配如何影响线粒体的输入和输出，以及这些变化如何影响基因活性和健康。我们将使用一种模式生物，果蝇，其中线粒体基因被故意错配到核基因组。这些果蝇具有已知的健康结果，如男性不育，但它们有缺陷的线粒体如何导致这些缺陷尚不清楚;出于同样的原因，可能改善其健康的治疗方法也是未知的。我们将使用尖端的实验方法来解决这些问题。具体来说，我们将在真实的时间内测量线粒体性能，以确定线粒体错配如何改变男性和女性生命过程中不同组织的功能，以及饮食治疗如何改变线粒体性能。我们将生成代谢物水平的全球概况，使我们能够将线粒体功能与每个组织的“代谢组学概况”联系起来。最后，我们将使用下一代测序技术来测量男性和女性每种组织中基因活性的变化。我们将利用这些信息建立一套数学模型，将线粒体功能的变化映射到代谢通量、基因活性和健康的变化，使我们能够概括我们的结论，对人类和动物的健康有价值。我们的初步研究表明，我们确实可以测量与男性不育相关的线粒体功能的实时变化。抗氧化剂治疗有显着不同的结果取决于线粒体不匹配，在一种情况下，提高男性生育能力，但导致高（90%）死亡率的女性苍蝇。因此，我们预计我们的发现将对终身健康产生重要影响。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development.

DOI：
10.7554/elife.69344
发表时间：
2021-07-19
期刊：
eLife
影响因子：
7.7
作者：
Colnaghi M;Pomiankowski A;Lane N
通讯作者：
Lane N

Genome expansion in early eukaryotes drove the transition from lateral gene transfer to meiotic sex.

DOI：
10.7554/elife.58873
发表时间：
2020-09-29
期刊：
eLife
影响因子：
7.7
作者：
Colnaghi M;Lane N;Pomiankowski A
通讯作者：
Pomiankowski A

Supplementary methods, results, 3 figures, and 1 table from A non-coding indel polymorphism in the

来自非编码插入缺失多态性的补充方法、结果、3 个图和 1 个表

DOI：
10.6084/m9.figshare.14529670
发表时间：
2021
期刊：
影响因子：
0
作者：
Jardine M
通讯作者：
Jardine M

Assessing the role of mitonuclear interactions on mitochondrial function and organismal fitness in natural Drosophila populations

DOI：
10.1101/2023.09.25.559268
发表时间：
2023-09
期刊：
bioRxiv
影响因子：
0
作者：
S. Bettinazzi;J. Liang;E. Rodriguez;M. Bonneau;R. Holt;B. Whitehead;D. Dowling;N. Lane;M. Camus
通讯作者：
S. Bettinazzi;J. Liang;E. Rodriguez;M. Bonneau;R. Holt;B. Whitehead;D. Dowling;N. Lane;M. Camus

Mother's curse is pervasive across a large mitonuclear Drosophila panel.