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FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

Lookup NU author(s): Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023 The Authors. Published under the terms of the CC BY 4.0 license.To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. 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-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F-box 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-associated mtDNA depletion syndrome.

Publication metadata

Author(s): Nguyen-Dien GT, Kozul K-L, Cui Y, Townsend B, Kulkarni PG, Ooi SS, Marzio A, Carrodus N, Zuryn S, Pagano M, Parton RG, Lazarou M, Millard SS, Taylor RW, Collins BM, Jones MJK, Pagan JK

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2023

Volume: 42

Online publication date: 10/05/2023

Acceptance date: 20/04/2023

Date deposited: 31/05/2023

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: John Wiley and Sons Inc


DOI: 10.15252/embj.2022112767


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust
Lily Foundation
Mito Foundation
MR/S005021/1Medical Research Council (MRC)
NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children
Pathological Society
NIHR Biomedical Research Centre for Ageing and Age-related disease