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Published February 13, 2025 | Version v1
Dataset Open

Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery

Authors/Creators

  • 1. Max Perutz Labs, Vienna Biocenter Campus (VBC), Dr.-Bohr-Gasse 9 / Vienna Biocenter 5, 1030, Vienna, Austria, University of Vienna, Max Perutz Labs, Department of Biochemistry and Cell Biology, Dr.-Bohr-Gasse 9 / Vienna Biocenter 5, 1030, Vienna, Austria
  • 2. California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
  • 3. Graduate Group in Biophysics, University of California, Berkeley, Berkeley, CA 94720, USA
  • 4. Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max-von-Laue-Str. 3, 60438, Frankfurt am Main, Germany
  • 5. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia, Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
  • 6. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
  • 7. Institute of Biophysics, Goethe University Frankfurt, 60438, Frankfurt am Main, Germany

Description

Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. While the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here, we demonstrate that transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI-ATG13 complex. This latter pathway is employed by the BNIP3/NIX receptors to trigger mitophagy. Additionally, other transmembrane mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use the FIP200/ULK1 complex, while FKBP8 and the ER-phagy receptor TEX264 are capable of utilising both pathways to initiate autophagy. Our study defines the molecular rules for initiation by transmembrane cargo receptors, revealing remarkable flexibility in the assembly and activation of the autophagy machinery, with significant implications for therapeutic interventions.

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Additional details

Funding

Aligning Science Across Parkinson's
Mechanisms of mitochondrial damage control by PINK1 and Parkin ASAP-000350