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Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation and mitochondrial damage. However, the mechanisms that govern the removal of specific dysfunctional mitochondria under steady\u2010state conditions to fine\u2010tune mitochondrial content are not well understood. Here, we report that SCF\n                    <jats:sup>FBXL4<\/jats:sup>\n                    , an SKP1\/CUL1\/F\u2010box protein ubiquitin ligase complex, localises to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that the pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13) do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism whereby FBXL4 actively suppresses mitophagy by preventing NIX and BNIP3 accumulation. We propose that the dysregulation of NIX and BNIP3 turnover causes excessive basal mitophagy in FBXL4\u2010associated mtDNA depletion syndrome.\n                  <\/jats:p>","DOI":"10.15252\/embj.2022112767","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T23:18:49Z","timestamp":1683760729000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":88,"title":["FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors"],"prefix":"10.1038","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3136-0485","authenticated-orcid":false,"given":"Giang Thanh","family":"Nguyen\u2010Dien","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5162-4807","authenticated-orcid":false,"given":"Keri\u2010Lyn","family":"Kozul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan","family":"Townsend","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0960-8237","authenticated-orcid":false,"given":"Prajakta Gosavi","family":"Kulkarni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Siang","family":"Ooi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Marzio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nissa","family":"Carrodus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Zuryn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Pagano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7494-5248","authenticated-orcid":false,"given":"Robert G","family":"Parton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lazarou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S Sean","family":"Millard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7768-8873","authenticated-orcid":false,"given":"Robert W","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6070-3774","authenticated-orcid":false,"given":"Brett M","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew JK","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7079-6388","authenticated-orcid":false,"given":"Julia K","family":"Pagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,10]]},"reference":[{"key":"BFEMBJ2022112767_CR1","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1038\/embor.2013.168","volume":"14","author":"GF Allen","year":"2013","unstructured":"Allen GF, Toth R, James J, Ganley IG (2013) Loss of iron triggers PINK1\/Parkin\u2010independent mitophagy. 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