Mitochondrial ROS mapping and control with sub-organellar resolution

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This project aims to advance our understanding of how mitochondria are able to retain their function under severe stress. Mitochondria are fundamental components of animal cells that are essential for proper cell metabolism and physiology. Mitochondrial dysfunction is linked to ageing, and to numerous human pathologies and so the maintenance of their normal function is very important. Mitochondria produce small molecules called reactive oxygen species (ROS) which are important for signalling in the cell but at high levels become highly damaging. The project will elucidate where within mitochondria ROS are produced, and how their levels are maintained. This will in turn allow us to understand better their localised effects as they are dictated by the internal mitochondrial architecture as a first step to develop efficient and targeted strategies to control them. This is absolutely critical because maintaining a fine balance of their levels makes all the difference for ROS being beneficial as signalling molecules in low levels or reverting to damaging agents for the cell at high levels.We will synthesise a series of small chemical molecules that can specifically detect distinct ROS and localise them in specific sub-mitochondrial compartments by targeting to these compartments selective protein tags that specifically attach to these probes. Under healthy conditions the import of these protein tags is powered by the mitochondrial transmembrane energy gradient. We have discovered that one antioxidant protein is imported by a system that does not require this energy gradient, which is remarkable and just as well since that gradient is compromised under severe redox stress conditions. We will make use of our knowledge of this new import pathway in compromised mitochondria to address for the first time the ROS distribution and effects in such damaged mitochondria. Our findings offer the first opportunity to explore the mechanisms of a previously elusive ROS distribution with unprecedented sub-mitochondrial resolution. This is critical to effectively defend cells against deleterious oxidative stress. Our interdisciplinary approach outlined in this project will further our understanding of mitochondrial targeting and cell stress mechanisms and it is likely to provide a novel paradigm for understanding the coordination of oxidative stress signalling in eukaryotic cells.