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Mechanistic studies of mitochondrial ferritin, a key player in iron mediated oxidative stress response and cellular iron metabolism

线粒体铁蛋白的机制研究，铁介导的氧化应激反应和细胞铁代谢的关键参与者

基本信息

批准号：
BB/R002363/1
负责人：
Nicolas Le Brun
金额：
$ 49.24万
依托单位：
University of East Anglia
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR002363%2F1
关键词：
Mechanistic studies mitochondrial ferritin key

项目摘要

Iron is essential for virtually all forms of life, playing central roles in many of the reactions on which life depends. In animals, including humans, many of the iron-containing cofactors that are essential are synthesized in a cellular organelle called the mitochondrion, which consequently has a high requirement for iron and can be regarded as the major cellular hub for iron metabolism. Despite its importance, we currently have a rather incomplete picture of how iron is regulated in mitochondria. An important player in this is mitochondrial ferritin, a member of the remarkable ferritin family of proteins. Ferritins can be thought of as being football-like molecules with a hollow centre in which thousands of iron atoms can be stored in the form of an iron mineral - one that would form insoluble precipitates were it not for the solubilising effect of the protein coat. The storage of iron serves two important functions. Firstly, it enables cells to draw on reserves when iron is low, and secondly, it overcomes the potential toxicity of iron that results from the very properties that make it useful to life: without proper control, iron can lead to the generation of reactive oxygen species that can cause severe cellular damage. The function of mitochondrial ferritin appears to be principally one of protecting against iron toxicity. Accordingly, it is only expressed in tissues that are metabolically highly active with a high turnover of oxygen, and consequently particularly susceptible to oxidative stress. These tissues include heart, testis and brain neurones, and it has been shown that this ferritin protects mitochondria in these cells from oxidative stress. It is presumed that it does this through the sequestration of potentially harmful excess free iron, but the details of this process are unclear. Mitochondrial ferritin also participates in the regulation of iron distribution between different cellular compartments, with increased levels of the protein associated with low cytosolic iron and cytosolic ferritin levels. The reason for this is currently not clear. Finally, mitochondrial ferritin is involved in pathogenesis of neurodegenerative diseases; its expression levels are increased in a range of disorders, including Parkinson's diseases, Alzheimer's disease, restless legs syndrome and Friedreich's ataxia, but its connection to these diseases is unclear.While studies of the in vivo roles of mitochondrial ferritin are increasing in scope and breadth, understanding of its mechanistic properties - how it interacts with iron and fulfils its cellular function - are lagging behind. Here, we propose a programme of research in which we will apply state of the art methodologies that will lead to important new information about how mitochondrial ferritin binds, oxidises and stores iron, and hence minimises its toxicity. Our preliminary studies have revealed that iron oxidation in mitochondrial ferritin involves protein-based radical formation. We will determine the role that the radical plays in mitochondrial ferritin and, in doing so, we will discover how it prevents the formation of reactive oxygen species that cause oxidative stress. We will also investigate iron release from mitochondrial ferritin, determining whether sequestered iron can be recycled. This will provide important new information about why the expression of mitochondrial ferritin causes iron deficiency in other cellular compartments.

铁对几乎所有形式的生命都是必不可少的，在生命所依赖的许多反应中发挥着核心作用。在包括人类在内的动物中，许多必需的含铁辅因子是在一种称为铁辅基的细胞器中合成的，因此对铁有很高的需求，可以被认为是铁代谢的主要细胞中心。尽管它的重要性，我们目前有一个相当不完整的图片铁是如何在线粒体中调节。其中一个重要的参与者是线粒体铁蛋白，它是蛋白质的显着铁蛋白家族的成员。铁蛋白可以被认为是具有中空中心的足球状分子，其中数千个铁原子可以以铁矿物的形式储存-如果不是蛋白质外壳的溶解作用，就会形成不溶性沉淀物。铁的储存有两个重要功能。首先，它使细胞能够在铁含量低时利用储备，其次，它克服了铁的潜在毒性，这种毒性来自于使其对生命有用的特性：如果没有适当的控制，铁可能导致产生活性氧，从而导致严重的细胞损伤。线粒体铁蛋白的功能似乎主要是保护免受铁毒性。因此，它仅在具有高氧转换的代谢高度活性的组织中表达，因此特别容易受到氧化应激的影响。这些组织包括心脏、睾丸和脑神经元，并且已经表明这种铁蛋白保护这些细胞中的线粒体免受氧化应激。据推测，这是通过螯合潜在有害的过量游离铁来实现的，但这一过程的细节尚不清楚。线粒体铁蛋白还参与调节不同细胞区室之间的铁分布，其中蛋白质水平的增加与低胞质铁和胞质铁蛋白水平相关。其原因目前尚不清楚。最后，线粒体铁蛋白参与神经退行性疾病的发病机制;它的表达水平在一系列疾病中增加，包括帕金森病、阿尔茨海默病、不宁腿综合征和弗里德赖希共济失调，但它与这些疾病的联系尚不清楚。虽然对线粒体铁蛋白体内作用的研究在范围和广度上都在增加，对它的机械特性--它如何与铁相互作用并实现其细胞功能--的理解还很落后。在这里，我们提出了一个研究计划，我们将应用最先进的方法，这将导致有关线粒体铁蛋白如何结合，氧化和储存铁的重要新信息，从而最大限度地减少其毒性。我们的初步研究表明，线粒体铁蛋白中的铁氧化涉及基于蛋白质的自由基形成。我们将确定自由基在线粒体铁蛋白中的作用，并在此过程中，我们将发现它如何阻止导致氧化应激的活性氧的形成。我们还将研究铁从线粒体铁蛋白中的释放，以确定螯合的铁是否可以回收。这将提供重要的新信息，为什么线粒体铁蛋白的表达会导致其他细胞室缺铁。

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）

Key carboxylate residues for iron transit through the prokaryotic ferritin SynFtn.

DOI：
10.1099/mic.0.001105
发表时间：
2021-11
期刊：
Microbiology (Reading, England)
影响因子：
0
作者：
Bradley JM;Fair J;Hemmings AM;Le Brun NE
通讯作者：
Le Brun NE

Bacterial iron detoxification at the molecular level.

DOI：
10.1074/jbc.rev120.007746
发表时间：
2020-12-18
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Bradley JM;Svistunenko DA;Wilson MT;Hemmings AM;Moore GR;Le Brun NE
通讯作者：
Le Brun NE

Iron Oxidation in Escherichia coli Bacterioferritin Ferroxidase Centre, a Site Designed to React Rapidly with H(2) O(2) but Slowly with O(2).

DOI：
10.1002/anie.202015964
发表时间：
2021-04-06
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
0
作者：
Pullin J;Wilson MT;Clémancey M;Blondin G;Bradley JM;Moore GR;Le Brun NE;Lučić M;Worrall JAR;Svistunenko DA
通讯作者：
Svistunenko DA

Protein encapsulation within the internal cavity of a bacterioferritin.