Rescuing mitochondria in peril by targeting of a critical antioxidant protein

该项目旨在促进我们对线粒体如何能够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至关重要。线粒体功能障碍与衰老和许多人类疾病有关，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。蛋白质输入线粒体对线粒体的构建至关重要。大多数线粒体蛋白（约占人类蛋白质组的10-15%）是在细胞质中合成的，因此必须在合成后进口。在健康条件下，大多数这些蛋白质的大部分进口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，因为这种能量梯度在这些严重的氧化还原应激条件下受到损害。我们的发现提供了第一个机会来探索这一全新的进口途径的机制，这是保护细胞免受有害氧化应激的关键。我们在本项目中概述的跨学科方法将进一步加深我们对线粒体蛋白输入和细胞应激机制的理解，并可能为理解真核细胞中氧化应激信号的协调提供新的范例。

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.