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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.

Original publication

DOI

10.1016/j.celrep.2017.08.087

Type

Journal article

Journal

Cell Rep

Publication Date

19/09/2017

Volume

20

Pages

2846 - 2859

Keywords

ARIH1, E3 ligase, PINK1, Parkin-independent, RBR-ligase, cell death, chemoresistance, lung cancer, mitophagy, mtKeima, Antineoplastic Agents, Autophagy, Carrier Proteins, Cell Death, Cell Line, Tumor, Cytoprotection, HeLa Cells, Humans, Mitochondria, Mitochondrial Degradation, Neoplasms, Protein Kinases, Protein Stability, Ubiquitin-Protein Ligases