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Cited by 53Autophagy in Disease and TherapyUbiquitin and proteasome pathwaysCalcium signaling and nucleotide metabolism

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

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Adriaenssens, Elias, Schaar, Stefan, Cook, Annan S. I., Stuke, Jan F. M., Sawa-Makarska, Justyna, Nguyen, Thanh Ngoc, Ren, Xuefeng, Schuschnig, Martina, Romanov, Julia, Khuu, Grace, Uoselis, Louise, Lazarou, Michael, Hummer, Gerhard, Hurley, James H., Martens, Sascha·2025·Nature Cell Biology
DOI 10.1038/s41556-025-01712-yPMC PMC12339401

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Abstract

Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. Although 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 the human 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, whereas FKBP8 and the ER-phagy receptor TEX264 are capable of utilizing 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 important implications for therapeutic interventions.

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Metadata

Authors
Adriaenssens, E., Schaar, S., Cook, A. S. I., Stuke, J. F. M., Sawa-Makarska, J., Nguyen, T. N., Ren, X., Schuschnig, M., Romanov, J., Khuu, G., Uoselis, L., Lazarou, M., Hummer, G., Hurley, J. H., & Martens, S.
Affiliations
  • University of Vienna (AT)
  • QB3 (US)
  • Max Planck Institute of Biophysics (DE)
  • The University of Melbourne (AU)
  • Goethe University Frankfurt (DE)
Corresponding author
  • Adriaenssens, Elias
  • Martens, Sascha
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2025-07-25
Volume
27
Issue
8
Pages
1272-1287
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/s41556-025-01712-y
PMC
PMC12339401
OpenAlex
W4412708007
Cited by
53
References
9
Citations by year
2026: 29 · 2025: 22
FWCI
35.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Cell Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Funders
  • Rebecca L. Cooper Medical Research Foundation (RC20241396)
  • National Institute of General Medical Sciences (R01GM129325)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
mitophagy, BNIP3, Nix, selective autophagy, autophagosome formation, FUNDC1, BCL2L13, FKBP8, ER-phagy, autophagy initiation

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