Mitochondrial redox protein quality control in ageing

衰老过程中线粒体氧化还原蛋白的质量控制

• 批准号: BB/W002892/1
• 负责人: Kostas Tokatlidis
• 金额: $ 67.82万
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW002892%2F1
• 关键词: Mitochondrial; redox; protein; quality; control

Mitochondria are fundamental components of animal cells that are essential for proper cell metabolism and physiology. To work properly mitochondria need to respond to stress and metabolic changes, adapt their protein content accordingly and adjust their function across the lifespan of an organism. Our project will address exactly these questions using simple yeast cells and fly models. Mitochondrial dysfunction is linked to ageing, and to numerous human pathologies and so the maintenance of their normal function is very important. Mitochondria produce small molecules called reactive oxygen species (ROS) which are important for signalling in the cell but at high levels become highly damaging. On the other hand, protein maintenance in mitochondria is subject to redox control but the details of this process are still elusive. In our project we will elucidate how a redox-dependent mechanism allows proper quality control of the proteins in mitochondria and how this in turns allows cell survival and proper development across the lifespan of an organism, particularly in the face of deleterious stresses. This is absolutely critical because maintaining a fine balance between redox proteins and ROS species makes all the difference for ROS being beneficial as signalling molecules in low levels or reverting to damaging agents for the cell at high levels.We will first investigate the function of a reductive machinery that we recently found to be targeted to the intermembrane space (IMS) between the outer and inner mitochondrial membranes. This could impact on either ensuring correct folding of proteins in the IMS or efficient clearance in case where they are misfolded. Then, we will ascertain how the redox machinery in the IMS provides a surveillance mechanism to maintain a balanced redox state not just for proteins but also for small metabolite molecules that are made in mitochondria and need to be released out of mitochondria as critical signalling molecules for the rest of the cell. Finally, we will use fly models to investigate at a whole organism level the role of those quality control mechanisms that preserve protein redox homeostasis in the IMS on lifespan. Our findings offer the first opportunity to explore a poorly characterised reductive pathway in mitochondria and its impact or redox homeostasis. This is critical to effectively defend cells against deleterious oxidative stress and sustain survival. The work is likely to provide a novel paradigm for understanding the coordination of protein redox control and oxidative stress signalling in eukaryotic cells and their effects on ageing.

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。为了正常工作，线粒体需要对压力和代谢变化做出反应，相应地调整其蛋白质含量，并在生物体的整个生命周期中调整其功能。我们的项目将使用简单的酵母细胞和苍蝇模型来解决这些问题。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。线粒体产生称为活性氧（ROS）的小分子，其对于细胞中的信号传导是重要的，但在高水平下变得高度破坏。另一方面，线粒体中的蛋白质维持受到氧化还原控制，但这一过程的细节仍然难以捉摸。在我们的项目中，我们将阐明氧化还原依赖性机制如何允许线粒体中蛋白质的适当质量控制，以及这反过来如何允许细胞在生物体的整个生命周期中存活和适当发育，特别是在面对有害压力时。这是绝对至关重要的，因为保持氧化还原蛋白和活性氧物种之间的良好平衡，使所有的差异，活性氧是有益的信号分子在低水平或恢复到破坏剂的细胞在高level.We将首先调查的功能，我们最近发现，以针对线粒体内外膜之间的膜间隙（IMS）的还原机制。这可能影响确保IMS中蛋白质的正确折叠或在它们错误折叠的情况下的有效清除。然后，我们将确定IMS中的氧化还原机制如何提供一种监视机制，以保持平衡的氧化还原状态，不仅是蛋白质，而且是线粒体中产生的小代谢物分子，需要从线粒体中释放出来作为细胞其余部分的关键信号分子。最后，我们将使用苍蝇模型，在整个生物体水平上调查的作用，这些质量控制机制，保持蛋白质氧化还原稳态IMS的寿命。我们的研究结果提供了第一次机会，探索线粒体中的还原途径及其影响或氧化还原稳态。这对于有效地保护细胞免受有害的氧化应激和维持生存至关重要。这项工作可能为理解真核细胞中蛋白质氧化还原控制和氧化应激信号的协调及其对衰老的影响提供一种新的范式。

项目成果

How the Disruption of Mitochondrial Redox Signalling Contributes to Ageing.

线粒体氧化还原信号的破坏如何导致衰老。

• DOI: 10.3390/antiox12040831
• 发表时间: 2023-03-29
• 期刊: ANTIOXIDANTS
• 影响因子: 7
• 作者: Castejon-Vega, Beatriz;Cordero, Mario D. D.;Sanz, Alberto
• 通讯作者: Sanz, Alberto

MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground

MIMAS 是线粒体巨型复合体游乐场中的新型巨型多功能玩家

• DOI: 10.1016/j.celrep.2024.113874
• 发表时间: 2024
• 期刊: Cell Reports
• 影响因子: 8.8
• 作者: Tokatlidis K

Neil J. Bulleid (1960-2023), a virtuoso of protein folding and redox biology.

Neil J. Bulleid (1960-2023)，蛋白质折叠和氧化还原生物学领域的大师。

• DOI: 10.15252/embj.2023115046
• 发表时间: 2023
• 期刊: The EMBO journal
• 作者: Braakman I

Mitochondria and Us: from exploration to global collective

线粒体与我们：从探索到全球集体

• DOI: 10.1042/bio_2022_122
• 发表时间: 2022
• 期刊: The Biochemist
• 作者: Caccavale E