Dissertation
Modulation of ferroptosis by various dietary fatty acids in C. elegans
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2021
DOI:
https://doi.org/10.7273/000003137
Handle:
https://hdl.handle.net/2376/122899
Abstract
Ferroptosis is an iron-dependent regulated form of cell death associated with oxidized fatty acids that cause uncontrolled lipid peroxidation and destruction of cell membranes. Roles of specific lipids in this process are not well understood. In this dissertation, we found that a dietary omega-6 polyunsaturated fatty acid (PUFA), dihomo-gamma-linolenic acid (DGLA; 20:3n6), causes death of germ cells through ferroptosis in the model organism Caenorhabditis elegans (C. elegans). Evidence for ferroptosis includes dependence of intracellular iron and inhibition by canonical ferroptosis inhibitors. Furthermore, we also found that DGLA causes cell death in cancer cells, showing induction of ferroptosis via this fatty acid is conserved. To investigate roles of other lipids influencing ferroptosis, we examined ether lipids, a class of phospholipid that are derived in the peroxisome and are attached to the glycerol backbone via an ether bond in the sn-1 position instead of a classical ester bond. In their absence, DGLA-induced ferroptosis of germ cells was accelerated. A subclass of ether lipids known as plasmalogens contain a vinyl ether bond and have been proposed to act as endogenous antioxidants. To examine the roles of plasmalogens in ferroptosis, we tested a mutant strain defective in plasmanylethanolamine desaturase activity. We found that plasmalogens do not play a significant role in ferroptosis. Instead, ether lipid deficient mutants display disrupted lipid homeostasis, with increased saturated fat and reduced monounsaturated fatty acids (MUFAs). We found that endogenous and exogenous MUFAs provide strong protection from ferroptosis. We also found that in the absence of endogenous 20-carbon PUFAs, ether lipids were not required for protection from ferroptosis. The work in this dissertation demonstrates the specificity of various fatty acids in inducing and inhibiting ferroptosis and adds to the growing knowledge of the field. Furthermore, this work highlights the power of using C. elegans to address biomedical questions in health and disease.
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Details
- Title
- Modulation of ferroptosis by various dietary fatty acids in C. elegans
- Creators
- Marcos Alejandro Perez
- Contributors
- Jennifer L. Watts (Advisor)John A. Browse (Committee Member)Erika G. Offerdahl (Committee Member)John Wyrick (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Molecular Biosciences, School of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 300
- Identifiers
- 99900651900501842
- Language
- English
- Resource Type
- Dissertation