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Cited by 47Autophagy in Disease and TherapyParkinson's Disease Mechanisms and TreatmentsUbiquitin and proteasome pathways

Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates

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Yang, Zi, Yoshii, Saori R, Sakai, Yuji, Zhang, Jing, Chino, Haruka, Knorr, Roland L, Mizushima, Noboru·2024·The EMBO Journal
DOI 10.1038/s44318-024-00272-5PMC PMC11574277

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Abstract

During PINK1- and Parkin-mediated mitophagy, autophagy adaptors are recruited to damaged mitochondria to promote their selective degradation. Autophagy adaptors such as optineurin (OPTN) and NDP52 facilitate mitophagy by recruiting the autophagy-initiation machinery, and assisting engulfment of damaged mitochondria through binding to ubiquitinated mitochondrial proteins and autophagosomal ATG8 family proteins. Here, we demonstrate that OPTN and NDP52 form sheet-like phase-separated condensates with liquid-like properties on the surface of ubiquitinated mitochondria. The dynamic and liquid-like nature of OPTN condensates is important for mitophagy activity, because reducing the fluidity of OPTN-ubiquitin condensates suppresses the recruitment of ATG9 vesicles and impairs mitophagy. Based on these results, we propose a dynamic liquid-like, rather than a stoichiometric, model of autophagy adaptors to explain the interactions between autophagic membranes (i.e., ATG9 vesicles and isolation membranes) and mitochondrial membranes during Parkin-mediated mitophagy. This model underscores the importance of liquid-liquid phase separation in facilitating membrane-membrane contacts, likely through the generation of capillary forces.

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  • OPTN recruits ATG9 vesicles to promote mitophagosome formation.

    “OPTN was further found to recruit ATG9 vesicles to promote mitophagosome formation [56].”

    From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [56]

  • OPTN and NDP52 form dynamic condensates on damaged mitochondria.

    “recent work has begun to position ATG9A at earlier stages of selective mitophagy initiation, demonstrating that OPTN and NDP52 form dynamic condensates on damaged mitochondria.”

    From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [56]

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Cited by

Sorted by citations

Authors
Yang, Z., Yoshii, S. R., Sakai, Y., Zhang, J., Chino, H., Knorr, R. L., & Mizushima, N.
Affiliations
  • Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
  • The University of Tokyo (JP)
  • Kyoto University (JP)
  • Harvard University (US)
  • University of Cologne (DE)
  • International Research Center for Neurointelligence, The University of Tokyo (JP)
Corresponding author
Mizushima, Noboru
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2024-10-17
Volume
43
Issue
22
Pages
5613-5634
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1038/s44318-024-00272-5
PMC
PMC11574277
OpenAlex
W4403503529
Cited by
47
References
3
Citations by year
2026: 27 · 2025: 17 · 2024: 3
FWCI
14.34
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • edoc Publication server (Humboldt University of Berlin) (submittedVersion, cc-by)
  • edoc Publication server (Humboldt University of Berlin) (cc-by)
Funders
  • MEXT | JST | Exploratory Research for Advanced Technology (JPMJER1702)
  • MEXT | Japan Society for the Promotion of Science (22H04919, 23K05715)
  • Deutsche Forschungsgemeinschaft (460056461)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
mitophagy, Parkin, PINK1, autophagy adaptors, optineurin, NDP52, liquid-liquid phase separation, isolation membrane, capillary forces, selective autophagy
MeSH terms
Autophagy-Related Proteins, Autophagy-Related Protein 8 Family, Autophagy, HeLa Cells, Humans, Membrane Proteins, Mitochondria, Nuclear Proteins, Cell Cycle Proteins, Membrane Transport Proteins, Vesicular Transport Proteins, Transcription Factor TFIIIA, Ubiquitin-Protein Ligases, Mitophagy

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