Plasticity of ether lipids promotes ferroptosis susceptibility and evasion View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-09-16

AUTHORS

Yilong Zou, Whitney S. Henry, Emily L. Ricq, Emily T. Graham, Vaishnavi V. Phadnis, Pema Maretich, Sateja Paradkar, Natalie Boehnke, Amy A. Deik, Ferenc Reinhardt, John K. Eaton, Bryan Ferguson, Wenyu Wang, Joshua Fairman, Heather R. Keys, Vlado Dančík, Clary B. Clish, Paul A. Clemons, Paula T. Hammond, Laurie A. Boyer, Robert A. Weinberg, Stuart L. Schreiber

ABSTRACT

Ferroptosis—an iron-dependent, non-apoptotic cell death process—is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers1. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions2–5. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR–Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome–ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis. More... »

PAGES

603-608

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41586-020-2732-8

    DOI

    http://dx.doi.org/10.1038/s41586-020-2732-8

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1130868432

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/32939090


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