RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells Journal Article
| Authors: | Hawk, M. A.; Gorsuch, C. L.; Fagan, P.; Lee, C.; Kim, S. E.; Hamann, J. C.; Mason, J. A.; Weigel, K. J.; Tsegaye, M. A.; Shen, L.; Shuff, S.; Zuo, J.; Hu, S.; Jiang, L.; Chapman, S.; Leevy, W. M.; Deberardinis, R. J.; Overholtzer, M.; Schafer, Z. T. |
| Article Title: | RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells |
| Abstract: | For cancer cells to survive during extracellular matrix (ECM) detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to reactive oxygen species (ROS) generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a role for receptor-interacting protein kinase 1 (RIPK1) in the modulation of ROS and cell viability during ECM detachment. We find that RIPK1 activation during ECM detachment results in mitophagy induction through a mechanism dependent on the mitochondrial phosphatase PGAM5. As a consequence of mitophagy, ECM-detached cells experience diminished NADPH production in the mitochondria, and the subsequent elevation in ROS levels leads to non-apoptotic death. Furthermore, we find that antagonizing RIPK1/PGAM5 enhances tumour formation in vivo. Thus, RIPK1-mediated induction of mitophagy may be an efficacious target for therapeutics aimed at eliminating ECM-detached cancer cells. © 2018 The Author(s). |
| Journal Title: | Nature Cell Biology |
| Volume: | 20 |
| Issue: | 3 |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-03-01 |
| Start Page: | 272 |
| End Page: | 284 |
| Language: | English |
| DOI: | 10.1038/s41556-018-0034-2 |
| PROVIDER: | scopus |
| PUBMED: | 29459781 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 April 2018 -- Source: Scopus |
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