FANCL supports Parkin-mediated mitophagy in a ubiquitin ligase-independent manner

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. The FA proteins have functions in genome maintenance and in the cytoplasmic process of selective autophagy, beyond their canonical roles of repairing DNA interstrand cross-links. FA core complex proteins FANCC, FANCF, FAN...

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Published in:Biochimica et biophysica acta. Molecular basis of disease 2022-09, Vol.1868 (9), p.166453-166453, Article 166453
Main Authors: Beesetti, Swarna, Sirasanagandla, Shyam, Sakurada, Sadie Miki, Pruett-Miller, Shondra M., Sumpter, Rhea, Levine, Beth, Potts, Malia B.
Format: Article
Language:English
Subjects:
FANCL
Fanconi anemia
Fanconi Anemia - genetics
Fanconi Anemia - metabolism
Fanconi Anemia Complementation Group L Protein
Fanconi Anemia Complementation Group Proteins - genetics
Fanconi Anemia Complementation Group Proteins - metabolism
HeLa Cells
Humans
Mitophagy
Parkin
Ubiquitin - metabolism
Ubiquitin ligase
Ubiquitin-Protein Ligases - genetics
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Summary:Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. The FA proteins have functions in genome maintenance and in the cytoplasmic process of selective autophagy, beyond their canonical roles of repairing DNA interstrand cross-links. FA core complex proteins FANCC, FANCF, FANCL, FANCA, FANCD2, BRCA1 and BRCA2, which previously had no known direct functions outside the nucleus, have recently been implicated in mitophagy. Although mutations in FANCL account for only a very small number of cases in FA families, it plays a key role in the FA pathophysiology and might drive carcinogenesis. Here, we demonstrate that FANCL protein is present in mitochondria in the control and Oligomycin and Antimycin (OA)-treated cells and its ubiquitin ligase activity is not required for its localization to mitochondria. CRISPR/Cas9-mediated knockout of FANCL in HeLa cells overexpressing parkin results in increased sensitivity to mitochondrial stress and defective clearing of damaged mitochondria upon OA treatment. This defect was reversed by the reintroduction of either wild-type FANCL or FANCL(C307A), a mutant lacking ubiquitin ligase activity. To summarize, FANCL protects from mitochondrial stress and supports Parkin-mediated mitophagy in a ubiquitin ligase-independent manner.
ISSN:0925-4439
1879-260X
DOI:10.1016/j.bbadis.2022.166453