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The role of mitochondrial oxidative damage in ageing: a chemical intervention approach

线粒体氧化损伤在衰老中的作用：化学干预方法

基本信息

批准号：
BB/D020786/1
负责人：
Linda Partridge
金额：
$ 87.7万
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：
2007
资助国家：
英国
起止时间：
2007 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FD020786%2F1
关键词：
role mitochondrial oxidative damage ageing

项目摘要

During ageing the human body becomes less able to do what it once could. The reason is that damage accumulates to the molecules of which cells are made up and to whole tissues. One common form of damage comes from oxygen, which is essential for breathing and respiration, but is also a danger to biological molecules. In cells, the energy-storage molecule ATP is produced in the mitochondria, by using oxygen to burn food supplies such as sugar and fats. When demand for energy is high, as for example during exercise, the mitochondria are not much of a problem. But when they have nothing to do because energy is not being consumed, they become much more likely to interact with oxygen to produce dangerous reactive molecules. These can go on to damage important biological molecules such as DNA and protein and the lipids in biological membranes, and this damage may be an important part of the ageing process. The damage is particularly likely to happen in the mitochondria themselves. So mitochondria may be key players in the ageing process, both as the site at which damaging molecules are produced and then as the main target of the damage that they cause. In this project we plan to develop and use chemicals that are targeted to the mitochondria to test these ideas and to try and intervene in the damage process. There is a charge across the surface of the mitochondria. We shall use a charged chemical 'tug' to drag biologically active molecules into the mitochondria. Some of these molecules act as reporters, for instance of the rate at which the mitochondria are generating the dangerous reactive molecules, the amount of damage that they are causing and the size of the charge across the surface of the mitochondria. Others protect against dangerous reactive molecules by detoxifying them. We shall test the efficacy of these molecules in a short-lived species, the fruit fly Drosophila, by adding them to the food. One of the advantages of Drosophila for this kind of work is that we can make long-lived strains, by feeding the flies on a restricted diet or making mutations in genes. We can therefore assess the role of mitochondrial damage in slowing down the ageing process in these long-lived strains. Ultimately, the goal of this work is to improve the health and quality of life of people as they age, and the aim of this project is to pave the way to the production of drugs that could achieve this goal.

在衰老过程中，人体会变得不能再做以前能做的事情。原因是损伤会累积到组成细胞的分子和整个组织。一种常见的损害形式来自氧气，氧气是呼吸和呼吸所必需的，但也对生物分子构成危险。在细胞中，储存能量的分子三磷酸腺苷是在线粒体中产生的，通过使用氧气燃烧糖和脂肪等食物供应。当能量需求很高时，例如在锻炼期间，线粒体不是太大的问题。但当它们因为能量没有被消耗而无事可做时，它们更有可能与氧气相互作用，产生危险的反应分子。它们会继续破坏重要的生物分子，如DNA和蛋白质，以及生物膜中的脂类，这种破坏可能是衰老过程的重要部分。这种损伤特别可能发生在线粒体本身。因此，线粒体可能是衰老过程中的关键角色，既是产生破坏性分子的地方，也是它们造成损害的主要目标。在这个项目中，我们计划开发和使用针对线粒体的化学物质来测试这些想法，并试图干预损伤过程。线粒体表面有一种电荷。我们将使用带电的化学“拖拽”将生物活性分子拖入线粒体。其中一些分子起到了报告的作用，例如，线粒体产生危险反应分子的速度，它们造成的损害程度，以及线粒体表面电荷的大小。另一些则通过解毒来保护它们免受危险的活性分子的伤害。我们将通过将这些分子添加到食物中来测试这些分子在一种短暂的物种--果蝇身上的效果。果蝇在这类工作中的优势之一是，我们可以通过限制饮食或对基因进行突变来制造长寿的品系。因此，我们可以评估线粒体损伤在减缓这些长寿菌株衰老过程中的作用。归根结底，这项工作的目标是随着年龄的增长改善人们的健康和生活质量，该项目的目的是为生产能够实现这一目标的药物铺平道路。

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）

Toward a control theory analysis of aging.

DOI：
10.1146/annurev.biochem.77.070606.101605
发表时间：
2008
期刊：
Annual review of biochemistry
影响因子：
16.6
作者：
Murphy MP;Partridge L
通讯作者：
Partridge L

Unraveling the biological roles of reactive oxygen species.

DOI：
10.1016/j.cmet.2011.03.010
发表时间：
2011-04-06
期刊：
Cell metabolism
影响因子：
29
作者：
Murphy MP;Holmgren A;Larsson NG;Halliwell B;Chang CJ;Kalyanaraman B;Rhee SG;Thornalley PJ;Partridge L;Gems D;Nyström T;Belousov V;Schumacker PT;Winterbourn CC
通讯作者：
Winterbourn CC

Fasting, but Not Aging, Dramatically Alters the Redox Status of Cysteine Residues on Proteins in Drosophila melanogaster.

DOI：
10.1016/j.celrep.2015.10.048
发表时间：
2015-11-10
期刊：
Cell reports
影响因子：
8.8
作者：
Menger KE;James AM;Cochemé HM;Harbour ME;Chouchani ET;Ding S;Fearnley IM;Partridge L;Murphy MP
通讯作者：
Murphy MP

[3-(Iodo-acetamido)prop-yl]triphenyl-phospho-nium tetra-phenyl-borate.

[3-(碘乙酰胺基)丙基]三苯基鏻四苯基硼酸盐。