Oral Presentation Hunter Cell Biology Meeting 2025

Initiation Mechanisms in PINK1/Parkin Mitophagy (119769)

Thanh N. Nguyen 1 2 3 4 , Justyna Sawa-Makarska 4 5 , Elias Adriaenssens 4 5 , Annan S.I. Cook 4 6 7 , Minghao Chen 4 7 8 , Ainara Claveras Cabezudo 4 9 10 , Gerhard Hummer 4 9 10 , James H. Hurley 4 6 7 8 11 , Michael Lazarou 1 2 3 4
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VICTORIA, Australia
  2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
  3. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
  4. Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD, USA
  5. Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna, Austria
  6. Graduate Group in Biophysics, University of California, Berkeley, Berkeley, CA, USA
  7. California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA
  8. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
  9. Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany
  10. IMPRS on Cellular Biophysics, Max Planck Institute of Biophysics, Frankfurt am Mai, Germany
  11. Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA

Mitochondria are essential organelles that generate the chemical energy required for cellular function. Beyond energy production, they regulate critical processes such as cell death, stem cell proliferation and maintenance, and immunity. However, damaged or dysfunctional mitochondria contribute to organismal aging and various diseases, including cancer, autoimmune disorders, and neurodegenerative conditions. This underscores the necessity of maintaining mitochondrial health for cellular homeostasis. Mitophagy, the selective degradation of dysfunctional mitochondria via lysosomes, is a key cellular strategy for preserving mitochondrial quality. Among the various mitophagy pathways, the PINK1/Parkin pathway has garnered significant attention due to its link to familial early-onset Parkinson’s disease. In this process, PINK1 and Parkin facilitate the formation of autophagosomes, double-membrane structures that encapsulate damaged mitochondria, preventing the release of toxic factors. These autophagosomes are subsequently delivered to lysosomes for degradation and recycling.

My research has provided critical insights into the molecular mechanisms governing PINK1/Parkin mitophagy, revealing how this pathway ensures efficient mitochondrial sequestration and degradation. Recently, we discovered that the PINK1/Parkin mitophagy pathway can be initiated via two distinct branches, rather than a single universal mechanism as previously thought (Nguyen et al., Molecular Cell 2023; Adriaenssens*, Nguyen* et al., Nature Structural & Molecular Biology 2024; *co-first authors). This highlights the mechanistic plasticity of selective autophagy pathways, demonstrating that even within the same type of selective autophagy, multiple initiation mechanisms can be employed depending on the available autophagy adaptors, which may vary across different cell types and tissues. Additionally, we identified a novel role of TBK1 as a ULK1-like initiating kinase that activates the PI3K complex. Despite its essential role in autophagy, the molecular mechanisms underlying PI3K complex regulation and activation remain poorly understood. In collaboration with the Hurley lab (UC Berkeley, USA) and the Hummer lab (Max Planck Institute, Germany), we recently visualized how the PI3K complex is kept inactive and switched on by its pseudokinase subunit, VPS15, upon autophagy induction (Cook*, Chen*, Nguyen*, Cabezudo* et al., Science 2025; co-first authors). These findings provide potential avenues for therapeutic targeting of mitophagy and autophagy pathways in neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease.