Ether lipid deficiency disrupts lipid homeostasis leading to ferroptosis sensitivity

PLoS Genet. 2022 Sep 30;18(9):e1010436. doi: 10.1371/journal.pgen.1010436. eCollection 2022 Sep.


Ferroptosis is an iron-dependent form of regulated cell death associated with uncontrolled membrane lipid peroxidation and destruction. Previously, we showed that dietary dihomo-gamma-linolenic acid (DGLA; 20: 3(n-6)) triggers ferroptosis in the germ cells of the model organism, Caenorhabditis elegans. We also demonstrated that ether lipid-deficient mutant strains are sensitive to DGLA-induced ferroptosis, suggesting a protective role for ether lipids. The vinyl ether bond unique to plasmalogen lipids has been hypothesized to function as an antioxidant, but this has not been tested in animal models. In this study, we used C. elegans mutants to test the hypothesis that the vinyl ether bond in plasmalogens acts as an antioxidant to protect against germ cell ferroptosis as well as to protect from whole-body tert-butyl hydroperoxide (TBHP)-induced oxidative stress. We found no role for plasmalogens in either process. Instead, we demonstrate that ether lipid-deficiency disrupts lipid homeostasis in C. elegans, leading to altered ratios of saturated and monounsaturated fatty acid (MUFA) content in cellular membranes. We demonstrate that ferroptosis sensitivity in both wild type and ether-lipid deficient mutants can be rescued in several ways that change the relative abundance of saturated fats, MUFAs and specific polyunsaturated fatty acids (PUFAs). Specifically, we reduced ferroptosis sensitivity by (1) using mutant strains unable to synthesize DGLA, (2) using a strain carrying a gain-of-function mutation in the transcriptional mediator MDT-15, or (3) by dietary supplementation of MUFAs. Furthermore, our studies reveal important differences in how dietary lipids influence germ cell ferroptosis versus whole-body peroxide-induced oxidative stress. These studies highlight a potentially beneficial role for endogenous and dietary MUFAs in the prevention of ferroptosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / metabolism
  • Animals
  • Antioxidants / metabolism
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Ether / metabolism
  • Fatty Acids, Monounsaturated / metabolism
  • Fatty Acids, Unsaturated
  • Ferroptosis* / genetics
  • Homeostasis / genetics
  • Iron / metabolism
  • Plasmalogens / metabolism
  • Vinyl Compounds
  • tert-Butylhydroperoxide / metabolism


  • Antioxidants
  • Fatty Acids, Monounsaturated
  • Fatty Acids, Unsaturated
  • Plasmalogens
  • Vinyl Compounds
  • Ether
  • vinyl ether
  • tert-Butylhydroperoxide
  • Iron
  • 8,11,14-Eicosatrienoic Acid