PINK1 and Parkin (PRKN), two genes linked to Parkinson's disease, have been strongly linked to the selective degradation of mitochondria (mitophagy). However, much of our current understanding comes from in vitro studies, and we still have a poor understanding of this process in a physiological context in vivo . PINK1 phosphorylates ubiquitin (pS65-Ub) on mitochondria to trigger mitophagy. We have recently developed protocols to detect PINK1 activity and monitor mitophagy under physiological conditions in vivo in Drosophila . With these quantitative mass spectrometry and immunodetection methods, we can now deeply analyse the spatiotemporal activation of the pathway in vivo by monitoring the level and localisation of pS65-Ub.
This project will investigate the mechanisms of Pink1 activation in Drosophila, in particular analysing the tissue specific distribution of pS65-Ub and mechanisms of degradation. Using state-of-the-art super-resolution microscopy, the project will also probe the sub-cellular distribution of pS65-Ub, addressing whether it may associate with sub-mitochondrial compartments in vivo. Importantly, we will also investigate the physiological mechanisms of stimuli. We are also interested in understanding the role that mitochondrial calcium plays in quality control processes , and this project would provide an opportunity to collaborate on these investigations. This project will shed new light on important mechanisms of mitochondrial quality control and potentially identify new targets for therapeutic interventions.
General: Mitochondria, Neurodegeneration, Mitophagy
More specific: PINK1, quality control, mass spectrometry, super-resolution microscopy, calcium, Drosophila
Research Group: https://www.mrc-mbu.cam.ac.uk/research-groups/whitworth-group