Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.
Nat Chem Biol
; 13(1): 81-90, 2017 Jan.
Article
in En
| MEDLINE
| ID: mdl-27842066
ABSTRACT
Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phospholipids
/
Arachidonic Acid
/
Fatty Acids, Unsaturated
Limits:
Animals
Language:
En
Journal:
Nat Chem Biol
Journal subject:
BIOLOGIA
/
QUIMICA
Year:
2017
Document type:
Article
Affiliation country:
Estados Unidos