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During iron deficiency, ferritin particles are transported to lysosomes to release iron ions. Two transport pathways have been reported: macroautophagy and ESCRT-dependent endosomal microautophagy. Although the membrane dynamics of these pathways differ, both require NCOA4, which is thought to be an autophagy receptor for ferritin. However, it is unclear whether NCOA4 only acts as an autophagy receptor in ferritin degradation. Here, we found that ferritin particles form liquid-like condensates in a NCOA4-dependent manner. Homodimerization of NCOA4 and interaction between FTH1 and NCOA4 (i.e., multivalent interactions between ferritin particles and NCOA4) were required for the formation of ferritin condensates. Disruption of these interactions impaired ferritin degradation. Time-lapse imaging and three-dimensional correlative light and electron microscopy revealed that these ferritin\u2013NCOA4 condensates were directly engulfed by autophagosomes and endosomes. In contrast, TAX1BP1 was not required for the formation of ferritin\u2013NCOA4 condensates but was required for their incorporation into autophagosomes and endosomes. These results suggest that NCOA4 acts not only as a canonical autophagy receptor but also as a driver to form ferritin condensates to facilitate the degradation of these condensates by macroautophagy (i.e., macroferritinophagy) and endosomal microautophagy (i.e., microferritinophagy).<\/jats:p>","DOI":"10.1083\/jcb.202203102","type":"journal-article","created":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T02:21:30Z","timestamp":1659579690000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":145,"title":["NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and microferritinophagy"],"prefix":"10.1083","volume":"221","author":[{"given":"Tomoko","family":"Ohshima","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayashi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan 1"},{"name":"Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuriko","family":"Sakamaki","sequence":"additional","affiliation":[{"name":"3Microscopy Research Support Unit, Research Core, Tokyo Medical and Dental University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4374-5120","authenticated-orcid":true,"given":"Chieko","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6258-6444","authenticated-orcid":true,"given":"Noboru","family":"Mizushima","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2022,9,6]]},"reference":[{"key":"2022112315312995600_bib1","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1038\/s41586-020-2992-3","article-title":"Wetting regulates autophagy of phase-separated compartments and the cytosol","volume":"591","author":"Agudo-Canalejo","year":"2021","journal-title":"Nature"},{"key":"2022112315312995600_bib2","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.cell.2018.12.035","article-title":"Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates","volume":"176","author":"Alberti","year":"2019","journal-title":"Cell"},{"key":"2022112315312995600_bib4","doi-asserted-by":"publisher","first-page":"2040","DOI":"10.1128\/MCB.01437-10","article-title":"Distinct mechanisms of ferritin delivery to lysosomes in iron-depleted and iron-replete cells","volume":"31","author":"Asano","year":"2011","journal-title":"Mol. 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