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Peroxisome-driven ether-linked phospholipids biosynthesis is essential for ferroptosis
- Source :
- Cell Death and Differentiation
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group UK, 2021.
-
Abstract
- It is well established that ferroptosis is primarily induced by peroxidation of long-chain poly-unsaturated fatty acid (PUFA) through nonenzymatic oxidation by free radicals or enzymatic stimulation of lipoxygenase. Although there is emerging evidence that long-chain saturated fatty acid (SFA) might be implicated in ferroptosis, it remains unclear whether and how SFA participates in the process of ferroptosis. Using endogenous metabolites and genome-wide CRISPR screening, we have identified FAR1 as a critical factor for SFA-mediated ferroptosis. FAR1 catalyzes the reduction of C16 or C18 saturated fatty acid to fatty alcohol, which is required for the synthesis of alkyl-ether lipids and plasmalogens. Inactivation of FAR1 diminishes SFA-dependent ferroptosis. Furthermore, FAR1-mediated ferroptosis is dependent on peroxisome-driven ether phospholipid biosynthesis. Strikingly, TMEM189, a newly identified gene which introduces vinyl-ether double bond into alkyl-ether lipids to generate plasmalogens abrogates FAR1-alkyl-ether lipids axis induced ferroptosis. Our study reveals a new FAR1-ether lipids-TMEM189 axis dependent ferroptosis pathway and suggests TMEM189 as a promising druggable target for anticancer therapy.
- Subjects :
- chemistry.chemical_classification
biology
Fatty acid
food and beverages
Endogeny
Cell Biology
Peroxisome
Cancer metabolism
Ether
Article
Lipoxygenase
chemistry.chemical_compound
Enzyme
Biochemistry
chemistry
Biosynthesis
Saturated fatty acid
biology.protein
Peroxisomes
Ferroptosis
Humans
lipids (amino acids, peptides, and proteins)
Molecular Biology
Phospholipids
Polyunsaturated fatty acid
Subjects
Details
- Language :
- English
- ISSN :
- 14765403 and 13509047
- Volume :
- 28
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Cell Death and Differentiation
- Accession number :
- edsair.doi.dedup.....120f506d10c48703fd1aaea03abad201