Rescuing mitochondria in peril by targeting of a critical antioxidant protein

通过靶向关键的抗氧化蛋白来拯救处于危险中的线粒体

• 批准号: BB/R009031/1
• 负责人: Kostas Tokatlidis
• 金额: $ 65.51万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR009031%2F1
• 关键词: Rescuing; mitochondria; peril; targeting; critical

This project aims to advance our understanding of how mitochondria are able to retain their function under severe stress. Mitochondria are fundamental components of animal cells that are essential for proper cell metabolism and physiology. Mitochondrial dysfunction is linked to ageing, and to numerous human pathologies and so the maintenance of their normal function is very important. The project will analyse how a critical antioxidant protein that normally resides in the cytoplasm is redirected into redox stressed mitochondria and how it is then able to ameliorate this stress. Protein import into mitochondria is essential for their construction. Most mitochondrial proteins (~10-15% of the human proteome) are synthesized in the cytosol and so must be imported following their synthesis. Under healthy conditions most of the import of most of these proteins is powered by the mitochondrial transmembrane energy gradient. Remarkably this antioxidant protein is imported by a system that does not require this energy gradient, which is just as well since that gradient is compromised under these severe redox stress conditions.Our findings offer the first opportunity to explore the mechanism of this entirely new import pathway that is critical to defend cells against deleterious oxidative stress. Our interdisciplinary approach outlined in this project will further our understanding of mitochondrial protein import and cell stress mechanisms and it is likely to provide a novel paradigm for understanding the coordination of oxidative stress signalling in eukaryotic cells.

该项目旨在促进我们对线粒体如何在严重压力下保持其功能的理解。线粒体是动物细胞的基本组成部分，对正常的细胞代谢和生理学至关重要。线粒体功能障碍与衰老和许多人类病理学有关，因此维持其正常功能非常重要。该项目将分析通常存在于细胞质中的关键抗氧化蛋白如何被重定向到氧化还原应激的线粒体中，以及它如何能够改善这种应激。蛋白质进入线粒体是其构建所必需的。大多数线粒体蛋白质（约占人类蛋白质组的10-15%）在细胞质中合成，因此必须在合成后输入。在健康条件下，这些蛋白质的大部分输入都是由线粒体跨膜能量梯度提供动力的。值得注意的是，这种抗氧化蛋白是由一个不需要这种能量梯度的系统输入的，这也是因为在这些严重的氧化还原应激条件下，这种梯度会受到损害。我们的研究结果首次提供了探索这种全新的输入途径的机制的机会，这种途径对于保护细胞免受有害的氧化应激至关重要。我们在这个项目中概述的跨学科方法将进一步我们的线粒体蛋白质进口和细胞应激机制的理解，它很可能提供一个新的范例，了解在真核细胞中的氧化应激信号的协调。

项目成果

Iron-sulfur clusters: from metals through mitochondria biogenesis to disease.

• DOI: 10.1007/s00775-018-1548-6
• 发表时间: 2018-06
• 期刊: Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry
• 作者: Cardenas-Rodriguez M;Chatzi A;Tokatlidis K
• 通讯作者: Tokatlidis K

The mitochondrial intermembrane space: the most constricted mitochondrial sub-compartment with the largest variety of protein import pathways.

• DOI: 10.1098/rsob.210002
• 发表时间: 2021-03
• 期刊: Open biology
• 影响因子: 5.8
• 作者: Edwards R;Eaglesfield R;Tokatlidis K
• 通讯作者: Tokatlidis K

Protein import in mitochondria biogenesis: guided by targeting signals and sustained by dedicated chaperones.

• DOI: 10.1039/d1ra04497d
• 发表时间: 2021-09-27
• 期刊: RSC advances
• 影响因子: 3.9

A Thioredoxin reductive mechanism balances the oxidative protein import pathway in the intermembrane space of mitochondria

硫氧还蛋白还原机制平衡线粒体膜间隙中的氧化蛋白输入途径

• DOI: 10.1101/2021.06.22.449413
• 发表时间: 2021
• 作者: Cardenas-Rodriguez M

Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells.

• DOI: 10.3389/fcell.2021.720656
• 发表时间: 2021
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Geldon S;Fernández-Vizarra E;Tokatlidis K
• 通讯作者: Tokatlidis K