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/R008167/2
• 负责人: Alberto Sanz Montero
• 金额: $ 22.32万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR008167%2F2
• 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.

英国人口的逐步老龄化是我们的社会在21世纪世纪面临的最严重的问题之一。患有与年龄有关的疾病的人数增加是NHS的沉重负担，并有可能使世界上最好的医疗保健系统之一崩溃。解决“老龄化问题”最简单和最具成本效益的办法是设法延缓衰老速度，延长健康寿命，推迟与年龄有关的疾病的发作，从而延长个人完全独立的时间。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。线粒体是细胞的发电站，产生大部分ATP，维持细胞运转所需的细胞货币。就像在任何其他工厂一样，线粒体产生有害废物，需要不时进行维护。自噬是细胞实现这一目标的主要途径。它负责清除和回收受损成分，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退行性变，并与帕金森病或阿尔茨海默病等疾病有关。我们发现了一种新的机制，将年龄相关的自噬效率降低与缺陷线粒体的积累联系起来。重要的是，这种机制可以用临床上已经使用的药物来靶向。当自噬被中断时，无论是在遗传上还是在衰老过程中，线粒体需要产生能量的呼吸复合物I（CI）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，这可能导致细胞死亡并加速衰老。我们已经发现，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项目，该项目将使用体外和体内模型的组合来建立自噬与衰老中线粒体之间的联系。首先，我们将研究如何在自噬缺陷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，我们将促进自噬和/或线粒体功能，以询问老年人的旁路CI是否足以延缓衰老。到这个项目结束时，我们将确定驱动衰老的关键机制，并可以用已经临床批准的疗法进行靶向治疗。

项目成果

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

Microsporidian obligate intracellular parasites subvert autophagy of infected mammalian host cells to promote their own growth

小孢子虫专性细胞内寄生虫破坏受感染哺乳动物宿主细胞的自噬以促进其自身生长

• DOI: 10.1101/2022.08.15.503970
• 发表时间: 2022
• 作者: Panek J

Editorial: "Mitochondrial coenzyme Q homeostasis: Signalling, respiratory chain stability and diseases.".

社论：“线粒体辅酶 Q 稳态：信号传导、呼吸链稳定性和疾病。”。

• DOI: 10.1016/j.freeradbiomed.2021.04.005
• 发表时间: 2021
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Navas P

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

Tryptophan stress activates EGFR-RAS-signaling to MTORC1 and p38/MAPK to sustain translation and AHR-dependent autophagy

色氨酸应激激活 EGFR-RAS 信号传导至 MTORC1 和 p38/MAPK，以维持翻译和 AHR 依赖性自噬

• DOI: 10.1101/2023.01.16.523931
• 发表时间: 2023
• 作者: Pfänder P