RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells

Mark A. Hawk, Cassandra L. Gorsuch, Patrick Fagan, Chan Lee, Sung Eun Kim, Jens C. Hamann, Joshua A. Mason, Kelsey J. Weigel, Matyas Abel Tsegaye, Luqun Shen, Sydney Shuff, Junjun Zuo, Stephan Hu, Lei Jiang, Sarah Chapman, W. Matthew Leevy, Ralph J. Deberardinis, Michael Overholtzer, Zachary T. Schafer

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)272-284
Number of pages13
JournalNature Cell Biology
Volume20
Issue number3
DOIs
StatePublished - Mar 1 2018

ASJC Scopus subject areas

  • Cell Biology

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    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. (2018). RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells. Nature Cell Biology, 20(3), 272-284. https://doi.org/10.1038/s41556-018-0034-2