Elcocks, Hannah and Brazel, Ailbhe J and McCarron, Katy R and Kaulich, Manuel and Husnjak, Koraljka and Mortiboys, Heather and Clague, Michael J and Urbé, Sylvie (2023) FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels. The EMBO Journal, 42 (13). ISSN 0261-4189

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Abstract

Selective autophagy of mitochondria, mitophagy, is linked to mitochondrial quality control and as such is critical to a healthy organism. We have used a CRISPR/Cas9 approach to screen human E3 ubiquitin ligases for influence on mitophagy under both basal cell culture conditions and upon acute mitochondrial depolarization. We identify two cullin‐RING ligase substrate receptors, VHL and FBXL4, as the most profound negative regulators of basal mitophagy. We show that these converge, albeit via different mechanisms, on control of the mitophagy adaptors BNIP3 and BNIP3L/NIX. FBXL4 restricts NIX and BNIP3 levels via direct interaction and protein destabilization, while VHL acts through suppression of HIF1α‐mediated transcription of BNIP3 and NIX. Depletion of NIX but not BNIP3 is sufficient to restore mitophagy levels. Our study contributes to an understanding of the aetiology of early‐onset mitochondrial encephalomyopathy that is supported by analysis of a disease‐associated mutation. We further show that the compound MLN4924, which globally interferes with cullin‐RING ligase activity, is a strong inducer of mitophagy, thus providing a research tool in this context and a candidate therapeutic agent for conditions linked to mitochondrial dysfunction.

Item Type:	Article
Additional Information:	Cite as: Elcocks, H., Brazel, A.J., McCarron, K.R., Kaulich, M., Husnjak, K., Mortiboys, H., Clague, M.J. & Urbé, S. 2023, "FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels", The EMBO journal, vol. 42, no. 13, pp. e112799-n/a.
Keywords:	Virology; AIDS Abstracts; mitophagy adaptors;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	17743
Identification Number:	https://doi.org/10.15252/embj.2022112799
Depositing User:	Ailbhe Brazel
Date Deposited:	26 Oct 2023 13:55
Journal or Publication Title:	The EMBO Journal
Publisher:	Blackwell Publishing Ltd
Refereed:	Yes
URI:
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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