Dietary Lipids Induce Ferroptosis in Caenorhabditiselegans and Human Cancer Cells

• Published in: Developmental cell 2020-08, Vol.54 (4), p.447-454.e4
• Main Authors: Perez, Marcos A., Magtanong, Leslie, Dixon, Scott J., Watts, Jennifer L.
• Format: Article
• Language: English
• Subjects: 8,11,14-Eicosatrienoic Acid - metabolism; 8,11,14-Eicosatrienoic Acid - pharmacology; Animals; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Cell Death - drug effects; Cell Differentiation - drug effects; Cell Line, Tumor; Dietary Fats - metabolism; Dietary Fats - pharmacology; ferroptosis; Ferroptosis - drug effects; germ cells; Germ Cells - drug effects; Homeostasis - drug effects; Humans; Iron - metabolism; Lipids - genetics; Lipids - pharmacology; Neoplasms - metabolism; Neoplasms - pathology; Phospholipids - pharmacology; polyunsaturated fatty acids
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2020.06.019

Dietary lipids impact development, homeostasis, and disease, but links between specific dietary fats and cell fates are poorly understood. Ferroptosis is an iron-dependent form of nonapoptotic cell death associated with oxidized polyunsaturated phospholipids. Here, we show that dietary ingestion of the polyunsaturated fatty acid (PUFA) dihomogamma-linolenic acid (DGLA; 20:3n-6) can trigger germ-cell ferroptosis and sterility in the nematode Caenorhabditis elegans. Exogenous DGLA is also sufficient to induce ferroptosis in human cells, pinpointing this omega-6 PUFA as a conserved metabolic instigator of this lethal process. In both C. elegans and human cancer cells, ether-lipid synthesis protects against ferroptosis. These results establish C. elegans as a powerful animal model to study the induction and modulation of ferroptosis by dietary fats and indicate that endogenous ether lipids act to prevent this nonapoptotic cell fate. [Display omitted] •Germ-cell death induced by dietary DGLA occurs via ferroptosis in C. elegans•Ferroptotic cell death is alleviated by antioxidants and iron chelators•DGLA specifically induces ferroptosis in human cancer cells•Ether lipids protect cells from DGLA-induced ferroptosis Ferroptosis is a form of regulated cell death associated with oxidized lipids. Perez et al. report that the ingestion of polyunsaturated fatty acids can trigger ferroptosis in C. elegans germ cells and human cancer cells. In both systems, endogenous ether lipids protect cells from ferroptotic cell death.