Poster Presentation 11th International Symposium on Autophagy 2025

Initiation mechanisms in PINK1/Parkin mitophagy (#223)

Thanh Nguyen 1 2 3 4 , Justyna Sawa-Makarska 3 5 , Elias Adriaenssens 3 5 , Annan SI Cook 3 6 7 , Minghao Chen 3 7 8 , Ainara C Cabezudo 3 9 10 , Gerhard Gerhard Hummer 3 9 10 11 , James H Hurley 3 6 7 8 , 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. Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD, USA
  4. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
  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. Institute of Biophysics, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany

Mitochondria are essential organelles that not only generate the chemical energy required for cellular function but also regulate critical processes such as cell death and immunity. However, dysfunctional mitochondria can contribute to organismal aging and various diseases, including cancer 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 (PD). In this process, PINK1/Parkin facilitate the formation of autophagosomes that encapsulate damaged mitochondria and deliver them to lysosomes for degradation.

My research has provided critical insights into the molecular mechanisms governing PINK1/Parkin mitophagy. Recently, we discovered that the PINK1/Parkin mitophagy can be initiated via two distinct branches, rather than one universal mechanism as previously thought (Nguyen et al. Mol Cell 2023; Adriaenssens*, Nguyen* et al. NSMB 2024; *co-first). This highlights the mechanistic plasticity of selective autophagy pathways, demonstrating that within the same type of selective autophagy, multiple initiation mechanisms can exist depending on the available autophagy adaptors, which may vary across different cell types and tissues. Additionally, we identified a novel role of TBK1 as an 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) and the Hummer lab (Max Planck Institute), 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). These findings provide potential avenues for therapeutic targeting of mitophagy and autophagy pathways in neurodegenerative diseases such as PD and ALS.