Role of Mitochondrial Reactive Oxygen Species in ageing and age-related diseases

线粒体活性氧在衰老和年龄相关疾病中的作用

• 批准号: 1960141
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-1960141
• 关键词: Role; Mitochondrial; Reactive; Oxygen; Species

Ageing and age-related diseases such as Parkinson's disease (PD) are characterized by the accumulation of defective mitochondria that produce fewer molecules of ATP and leak more free radicals. Cells possess quality control mechanisms that remove defective mitochondria. Why and how defective organelles accumulate in aged individuals remains unknown. The most widely accepted explanation is that the age associated increase in levels of reactive oxygen species (ROS) is responsible for the deficient mitochondria found in aged tissues. In contrast to this however, boosting ROS levels has been shown to extend lifespan in animal models. Recently, we have shown that elimination of damaged mitochondria prevents cellular senescence, whereas specifically increasing ROS produced by respiratory complex I protects mitochondrial function and extends lifespan in Drosophila melanogaster. We propose that signalling activated by ROS produced via complex I is required for turnover of damaged mitochondria. We hypothesize that when this signalling is interrupted during ageing (or in diseases where complex I are implicated such as PD) mitochondrial turnover is halted and ROS accumulate causing mitochondrial damage. These damaged mitochondria release mitochondrial DNA, proteins and metabolites, triggering inflammation, promoting oxidative damage and reducing autophagy via activation of Tor. Therefore, we propose that stimulating complex I activity, eliminating damaged mitochondria and preventing the leak of pro-inflammatory mitochondrial components will extend lifespan and protect against neurodegeneration. The student will test the main hypothesis using three approaches: in vivo (Drosophila models of normal ageing and PD), in vitro (mammalian models of cellular senescence) and in silico (using RNA sequencing analysis). Upon completion, the student will have skills in molecular biology, imaging, physiology and big data analysis. This experience of diverse technologies and approaches will allow the student to pursue a successful scientific career.

衰老和与年龄相关的疾病，如帕金森病（PD）的特征是有缺陷的线粒体的积累，产生更少的ATP分子和泄漏更多的自由基。细胞具有去除缺陷线粒体的质量控制机制。为什么以及如何有缺陷的细胞器在老年人中积累仍然未知。最广泛接受的解释是，与年龄相关的活性氧（ROS）水平的增加是衰老组织中发现的线粒体缺陷的原因。然而，与此相反，提高ROS水平已被证明可以延长动物模型的寿命。最近，我们已经表明，消除受损的线粒体可以防止细胞衰老，而特异性增加呼吸复合物I产生的ROS可以保护线粒体功能并延长果蝇的寿命。我们建议，通过复合物I产生的活性氧激活的信号是受损线粒体的周转所需的。我们假设，当这种信号传导在衰老过程中（或在涉及复合物I的疾病中，如PD）中断时，线粒体周转停止，ROS积累，导致线粒体损伤。这些受损的线粒体释放线粒体DNA、蛋白质和代谢物，引发炎症，促进氧化损伤，并通过Tor的激活减少自噬。因此，我们建议刺激复合物I活性，消除受损的线粒体并防止促炎线粒体成分的泄漏将延长寿命并防止神经退行性变。学生将使用三种方法测试主要假设：体内（正常衰老和PD的果蝇模型），体外（细胞衰老的哺乳动物模型）和计算机（使用RNA测序分析）。完成后，学生将掌握分子生物学，成像，生理学和大数据分析方面的技能。这种不同的技术和方法的经验将使学生追求成功的科学事业。