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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.
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
URL: https://doi.org/10.15252/embj.2022112767
DOI: 10.15252/embj.2022112767
Data Access Statement: This study includes no data deposited in external repositories.
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