Journal
EMBO JOURNAL
Volume 42, Issue 13, Pages -Publisher
WILEY
DOI: 10.15252/embj.2022112799
Keywords
BNIP3; FBXL4; mitophagy; NIX; VHL
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Selective autophagy of mitochondria, mitophagy, is critical to maintain mitochondrial quality control. Through a CRISPR/Cas9 approach, we identified two proteins, VHL and FBXL4, which act as negative regulators of basal mitophagy by controlling the levels of mitophagy adaptors BNIP3 and BNIP3L/NIX via different mechanisms. Depletion of NIX, but not BNIP3, restores mitophagy levels, providing insights into the pathogenesis of early-onset mitochondrial encephalomyopathy. We also found that a compound called MLN4924 can induce mitophagy, making it a potential therapeutic agent for mitochondrial dysfunction-related conditions.
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 HIF1 alpha-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.
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