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

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1868; no. 9; p. 166453
• Main Authors: Beesetti, Swarna, Sirasanagandla, Shyam, Sakurada, Sadie Miki, Pruett-Miller, Shondra M., Sumpter, Rhea, Levine, Beth, Potts, Malia B.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2022
• 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; Fanconi anemia; Ubiquitin ligase; Mitophagy; FANCL; Parkin
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2022.166453

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.