CDB Seminar - Dr Alex Whitworth, MRC Mitochondrial Biology Unit, University of Cambridge

Zoom: https://ucl.zoom.us/j/91053572127

Talk abstract: Maintaining the normal function of our most active tissues, such as the brain and heart, throughout decades of a human lifespan presents an extraordinary biological challenge. Mitochondria are central to the life and death of these tissues and have long been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD). Early functional analyses of two genes linked to Parkinson's disease, PINK1 and Parkin (PRKN), established that they play an important role in mitochondrial homeostasis. Numerous studies have since implicated the PINK1-Parkin pathway in many steps of mitochondrial quality control including fission/fusion dynamics and intracellular trafficking to autophagic degradation (mitophagy), however, the physiological in vivo evidence supporting defective mitophagy in pathogenesis is limited. Nevertheless, disrupted mitochondrial homeostasis has the potential to impact on multiple aspects of mitochondrial physiology and ultimately on neuronal survival. The work in our lab investigates the cellular mechanisms underlying neurodegenerative diseases, in order to identify potential therapeutic intervention points, primarily using Drosophila as a model system. I will present our recent advances in understanding the physiological requirements of PINK1/Parkin in regulating mitochondrial homeostasis and the implications this might have for combating neurodegeneration.

Suggested references:

Parkin drives pS65-Ub turnover independently of canonical autophagy in Drosophila. Usher JL, Sanchez-Martinez A, Terriente-Felix A, Chen PL, Lee JJ, Chen CH, Whitworth AJ.EMBO Rep. 2022 Dec 6;23(12):e53552. doi: 10.15252/embr.202153552.

Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models. Twyning MJ, Tufi R, Gleeson TP, Kolodziej KM, Campesan S, Terriente-Felix A, Collins L, De Lazzari F, Giorgini F, Whitworth AJ.Cell Rep. 2024 Feb 27;43(2):113681. doi: 10.1016/j.celrep.2024.113681.

Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models. Martinez A, Sanchez-Martinez A, Pickering JT, Twyning MJ, Terriente-Felix A, Chen PL, Chen CH, Whitworth AJ.Mol Neurodegener. 2024 Jan 25;19(1):12. doi: 10.1186/s13024-024-00701-3.

Host: Michael Duchen, UCL CDB