WEHI Wednesday Seminar hosted by Professor Michael Lazarou
 

Dr Wai Kit (Leo) Lam

Research Officer – Lazarou Laboratory, Ubiquitin Signalling division, WEHI

PINK1／Parkin mitophagy: From neurodegenerative mechanisms to a therapeutic avenue 

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Neurons are highly susceptible to mitochondrial dysfunction due to their post-mitotic nature and high metabolic demands. Mitophagy, an important mitochondrial quality control mechanism, selectively captures and delivers damaged mitochondria to lysosomes for degradation. The protein kinase PINK1 and the E3 ubiquitin ligase Parkin are key initiators of damage-induced mitophagy, and mutations in these proteins are associated with autosomal recessive early-onset Parkinson’s disease (PD). Oxidative stress, resulting from dysfunctional mitochondria, is a core contributor to neurodegeneration in PD. While mitophagy is essential for maintaining mitochondrial quality, the mechanisms by which mitophagy is regulated in neurons, particularly under mild oxidative stress, remain poorly understood. Furthermore, axonal degeneration is thought to be a primary event in PD pathogenesis, yet the role of mitophagy in this context is not known.

In this study, we address three fundamental questions: 1) How are damaged mitochondria recognised and eliminated by PINK1/Parkin mediated mitophagy in axons? 2) What are the consequences of a breakdown in PINK1/Parkin-mediated mitophagy? 3) Can the effects of PINK1/Parkin mitophagy defects be rescued by promoting an alternative mitophagy pathway, such as NIX/BNIP3-dependent mitophagy? Our findings show that axonal PINK1/Parkinmediated mitophagosome formation primarily occurs at presynapses, and uncover a neurodegenerative mechanism linking axonal vulnerabilities observed in PD with mitophagy defects. Excitingly, we also demonstrate that pharmacological rescue of axonal degeneration can be achieved by synthetic upregulation of receptor-mediated mitophagy using the clinically approved compound Roxadustat, revealing a potential therapeutic avenue for PD. Collectively, these findings enhance our understanding of how mitophagy machinery maintains neuronal health and guide the development of mitophagy modulators as potential PD therapeutics.

All welcome!