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

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.