DiMeN Doctoral Training Partnership: Role of Mitochondrial Reactive Oxygen Species in ageing and age-related diseases

Nowadays, one of the main biomedical problems that the United Kingdom will confront is the increase in its ageing population. Ageing and age-associated diseases such as Parkinson’s disease (PD) limit the independence of the elderly and place a heavy burden on health-care. The MRC recognises that the most efficient way to tackle the ageing process is to understand what fails in old age and identify ways to delay, prevent or reverse deleterious age-related changes. One universal hallmark of ageing and many neurodegenerative diseases (such as PD) is the accumulation of damaged mitochondria and increased inflammation, therefore boosting mitochondrial function and/or reducing inflammation in aged individuals should extend healthy lifespan and delay the onset of age-related diseases.

Mitochondria are the powerhouses of the cell producing most of the energy the cell needs. While generating energy, toxic by-products are produced in the form of free radicals also known as Reactive Oxygen Species (ROS). Damaged mitochondria that accumulate during ageing and those present in the brain of PD patients produce more ROS contributing to increased inflammation, oxidative stress and cell death. However, ROS play an essential role in differentiation, autophagy, hypoxia and activation of the immune system. Therefore, how ROS contribute to ageing and the onset of age-related disease remains to be established. Recently, the Sanz Lab made a seminal discovery showing that activation of a ROS signalling produced via Reverse Electron Transport (RET) at respiratory complex I extended lifespan of Drosophila melanogaster and protected mitochondrial function in a Drosophila Parkinson’s disease model (Cell Metabolism, 2016, 107(20):9105-10). Moreover suppression of ROS produced via RET results in the accumulation of damaged mitochondria and accelerates ageing. Interestingly, the Passos lab has shown that elimination of damaged mitochondria reduces inflammation and through this prevents cellular senescence, known to shorten lifespan (EMBO, 2016, 35(7):724-42).

We hypothesize that ROS produced via RET is the main mechanism responsible for turnover of damaged mitochondria. When this ROS signal is interrupted, inflammation is triggered resulting in cell death (e.g. neurons of the substantia nigra in PD patients) and acceleration of ageing. We predict that RET-ROS signalling is reduced during ageing, and that boosting RET derived ROS will protect mitochondrial function, prevent inflammation and extend health span. Moreover, the work of the De Magalhaes lab has defined transcriptomic signatures which reflect changes in ageing rate (Genome Biol., 2015, 16:285) and allow prediction of which factors will accelerate or delay ageing.

The successful candidate will test our working model, contributing to a better understanding of the role of mitochondria in ageing and neurodegenerative diseases such as PD. Moreover it is expected that as a result of this PhD, new therapies to prevent, delay and reverse ageing will be discovered. The successful candidate will use three different approaches: in vivo (using Drosophila melanogaster specimens), in vitro (using mammalian cells) and in silico (using computational techniques). The student will be trained in the state-of-the-art molecular biology techniques (including genome editing using CRISPR-Cas9), imaging technology (high-resolution microscopy to detect ROS levels in vivo) and big data analysis (using RNA-sequence). This comprehensive training will provide the student with the skills needed pursue an academic or industrial career after graduation.

Newcastle University and the University of Liverpool offer a unique environment for ageing research within campuses that develop world leading research. The labs of all three supervisors are well funded by the UK Research Councils and have a track record of publishing in top tier journals in the field of ageing including Cell Metabolism, PNAS, EMBO J, Nature Communications and Genome Biology.