Role of autophagy in the accumulation of defective mitochondria during ageing

自噬在衰老过程中缺陷线粒体积累中的作用

• 批准号: BB/R008167/1
• 负责人: Alberto Sanz Montero
• 金额: $ 41.92万
• 依托单位: Newcastle University
• 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%2FR008167%2F1
• 关键词: Role; autophagy; accumulation; defective; mitochondria

The progressive ageing of the UK population is one of the most serious problems our society will face during the 21st century. The increase in the number of people suffering from age-related diseases is a heavy burden on the NHS and threatens to collapse one of the best health care systems in the world. The simplest and most cost effective solution to the "ageing problem" is to find ways to delay the rate of ageing, extending healthy lifespan, delaying the onset of age-related diseases and therefore extending the time an individual can remain fully independent. To delay ageing, we must fully understand the complex mechanisms that drive it and how they are connected. Mitochondria are the powerhouses of the cell, generating the majority of ATP, the cellular currency required to keep cells going. As in any other factory, mitochondria generate harmful waste and require maintenance from time to time. Autophagy is the main way that the cell achieves this. It is responsible for removal and recycling of damaged components to keep the cell, including mitochondria, in optimal working condition. With age, the capacity of autophagy to do this declines. At the same time damaged mitochondria also accumulate, causing depletion of ATP, which leads to cell death and neurodegeneration and is associated with diseases such as Parkinson's or Alzheimer's disease.We have found a new mechanism that connects the age associated reduction in autophagy efficiency and the accumulation of defective mitochondria. Importantly this mechanism can be targeted with drugs that are already in use in the clinic. When autophagy is interrupted, either genetically or during aging, respiratory complex I (CI) which mitochondria need to produce energy, stops working properly and starts to generate an abnormally high amount of harmful waste in the form of free radicals which can cause cell death and accelerate ageing. We have discovered that by-passing CI or restoring its function prevents cell death and extends lifespan. We will develop a research program that will use a combination of in vitro and in vivo models to establish the connection between autophagy and mitochondria in ageing. Firstly, we will investigate how cell death is induced in autophagy-deficient cells, restoring CI function and rescuing cell death. Secondly, we will use the powerful genetics of the fruit fly to find out how loss of autophagy causes the accumulation of damaged mitochondria and measure it effect on the ageing process. Finally, we will boost autophagy and/or mitochondrial function to ask if by-passing CI in old individuals is enough to delay ageing. By the end of this project, we will have identified key mechanisms that drive ageing and can be targeted with therapies which are already clinically approved.

英国人口的逐渐老龄化是我们社会在21世纪将面临的最严重的问题之一。患有与年龄相关疾病的人数增加给国民医疗服务体系（NHS）带来了沉重负担，并有可能导致世界上最好的医疗保健系统之一崩溃。解决“衰老问题”最简单、最具成本效益的方法是找到延缓衰老速度、延长健康寿命、延缓与年龄相关疾病发生的方法，从而延长个人保持完全独立的时间。为了延缓衰老，我们必须充分了解驱动衰老的复杂机制以及它们之间的联系。线粒体是细胞的动力源，产生大部分 ATP，这是维持细胞运转所需的细胞货币。与任何其他工厂一样，线粒体会产生有害废物，需要不时进行维护。自噬是细胞实现这一目标的主要方式。它负责清除和回收受损的成分，以保持细胞（包括线粒体）处于最佳工作状态。随着年龄的增长，自噬的能力会下降。与此同时，受损的线粒体也会积累，导致 ATP 耗尽，从而导致细胞死亡和神经变性，并与帕金森病或阿尔茨海默病等疾病有关。我们发现了一种新机制，将年龄相关的自噬效率降低与有缺陷的线粒体的积累联系起来。重要的是，这种机制可以针对临床上已经使用的药物。当自噬因遗传因素或衰老过程而中断时，线粒体产生能量所需的呼吸复合物 I (CI) 就会停止正常工作，并开始以自由基的形式产生异常大量的有害废物，从而导致细胞死亡并加速衰老。我们发现绕过 CI 或恢复其功能可以防止细胞死亡并延长寿命。我们将开发一个研究计划，结合体外和体内模型来建立衰老过程中自噬和线粒体之间的联系。首先，我们将研究如何在自噬缺陷的细胞中诱导细胞死亡，恢复 CI 功能并挽救细胞死亡。其次，我们将利用果蝇强大的遗传学来找出自噬的丧失如何导致受损线粒体的积累，并测量其对衰老过程的影响。最后，我们将增强自噬和/或线粒体功能，以探讨绕过老年个体的 CI 是否足以延缓衰老。到该项目结束时，我们将确定导致衰老的关键机制，并可以针对已获得临床批准的疗法进行靶向治疗。

项目成果

NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy.

• DOI: 10.15252/embj.2022111372
• 发表时间: 2023-03-01
• 期刊: The EMBO journal

Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies.

• DOI: 10.1007/s11357-022-00555-x
• 发表时间: 2022-08
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Graham, Charlotte;Stefanatos, Rhoda;Yek, Angeline E. H.;Spriggs, Ruth, V;Loh, Samantha H. Y.;Uribe, Alejandro Huerta;Zhang, Tong;Martins, L. Miguel;Maddocks, Oliver D. K.;Scialo, Filippo;Sanz, Alberto
• 通讯作者: Sanz, Alberto

Nutrient sensing, growth and senescence.

• DOI: 10.1111/febs.14400
• 发表时间: 2018-06
• 期刊: The FEBS journal
• 作者: Carroll B;Korolchuk VI
• 通讯作者: Korolchuk VI

Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis.

SQSTM1/p62的氧化介导了氧化还原状态与蛋白质稳态之间的联系。

• DOI: 10.1038/s41467-017-02746-z
• 发表时间: 2018-01-17
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Carroll B;Otten EG;Manni D;Stefanatos R;Menzies FM;Smith GR;Jurk D;Kenneth N;Wilkinson S;Passos JF;Attems J;Veal EA;Teyssou E;Seilhean D;Millecamps S;Eskelinen EL;Bronowska AK;Rubinsztein DC;Sanz A;Korolchuk VI
• 通讯作者: Korolchuk VI

L-Carnitine in Drosophila: A Review.

• DOI: 10.3390/antiox9121310
• 发表时间: 2020-12-21
• 期刊: Antioxidants (Basel, Switzerland)
• 作者: Carillo MR;Bertapelle C;Scialò F;Siervo M;Spagnuolo G;Simeone M;Peluso G;Digilio FA
• 通讯作者: Digilio FA