Reference - Detail
| RRC ID | 82774 |
|---|---|
| Author | Yang Z, Yoshii SR, Sakai Y, Zhang J, Chino H, Knorr RL, Mizushima N. |
| Title | Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates. |
| Journal | EMBO J |
| 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. |
| Volume | 43(22) |
| Pages | 5613-5634 |
| Published | 2024-11-1 |
| DOI | 10.1038/s44318-024-00272-5 |
| PII | 10.1038/s44318-024-00272-5 |
| PMID | 39420095 |
| PMC | PMC11574277 |
| MeSH | Autophagy Autophagy-Related Protein 8 Family / genetics Autophagy-Related Protein 8 Family / metabolism Autophagy-Related Proteins* / genetics Autophagy-Related Proteins* / metabolism Cell Cycle Proteins* / genetics Cell Cycle Proteins* / metabolism HeLa Cells Humans Membrane Proteins Membrane Transport Proteins* / genetics Membrane Transport Proteins* / metabolism Mitochondria* / metabolism Mitophagy* Nuclear Proteins / genetics Nuclear Proteins / metabolism Transcription Factor TFIIIA* / genetics Transcription Factor TFIIIA* / metabolism Ubiquitin-Protein Ligases* / genetics Ubiquitin-Protein Ligases* / metabolism Vesicular Transport Proteins |
| Resource | |
| DNA material | pMRX-IPU-muGFP-OPTN delta UBAN (RDB20078) pMRX-IPU-muGFP-OPTN (RDB20079) pMRX-IPU-muGFP-Ubiquitin (RDB20080) pMRX-IPU-muGFP-p62 (RDB20081) pMRX-IPU-muGFP-NBR1 (RDB20082) pMRX-IPU-muGFP-NDP52 (RDB20083) pMRX-IPU-muGFP-TAX1BP1 (RDB20084) |