Parkin-Independent Mitophagy Controls Chemotherapeutic Response in Cancer Cells

• Published in: Cell reports (Cambridge) Vol. 20; no. 12; pp. 2846 - 2859
• Main Authors: Villa, Elodie, Proïcs, Emma, Rubio-Patiño, Camila, Obba, Sandrine, Zunino, Barbara, Bossowski, Jozef P., Rozier, Romain M., Chiche, Johanna, Mondragón, Laura, Riley, Joel S., Marchetti, Sandrine, Verhoeyen, Els, Tait, Stephen W.G., Ricci, Jean-Ehrland
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.09.2017; Elsevier
• Subjects: Antineoplastic Agents - pharmacology; ARIH1; Autophagy - drug effects; Carrier Proteins - metabolism; cell death; Cell Death - drug effects; Cell Line, Tumor; chemoresistance; Cytoprotection - drug effects; E3 ligase; HeLa Cells; Humans; lung cancer; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Degradation - drug effects; mitophagy; mtKeima; Neoplasms - metabolism; Neoplasms - pathology; Parkin-independent; PINK1; Protein Kinases - metabolism; Protein Stability - drug effects; RBR-ligase; Ubiquitin-Protein Ligases - metabolism; lung cancer; mitophagy; RBR-ligase; chemoresistance; PINK1; E3 ligase; cell death; mtKeima; Parkin-independent; ARIH1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.08.087

Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. Because the main known regulators of mitophagy are frequently inactivated in cancer cells, the mechanisms that regulate mitophagy in cancer cells are not fully understood. Here, we identified an E3 ubiquitin ligase (ARIH1/HHARI) that triggers mitophagy in cancer cells in a PINK1-dependent manner. We found that ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal via autophagy. Importantly, ARIH1 is widely expressed in cancer cells, notably in breast and lung adenocarcinomas; ARIH1 expression protects against chemotherapy-induced death. These data challenge the view that the main regulators of mitophagy are tumor suppressors, arguing instead that ARIH1-mediated mitophagy promotes therapeutic resistance. [Display omitted] •Parkin (RBR E3 ligase) is absent in most cancer cells when mitophagy is functional•ARIH1, an E3 ligase belonging to the RBR family, is expressed in cancer cells•ARIH1 controls mitophagy of damaged mitochondrial in a PINK1-dependent manner•ARIH1’s control of mitophagy protects cancer cells from chemotherapy-induced death Clearance of damaged mitochondria (mitophagy) is involved in the resistance to chemotherapeutic-induced death, but the main known regulators of mitophagy are not expressed in cancer cells. Villa et al. show that the RBR E3 ligase ARIH1 is expressed in several cancer cell types. ARIH1 controls PINK1-dependent mitophagy and sensitivity to chemotherapies.