Arginine Expedites Erastin-Induced Ferroptosis through Fumarate.
Int J Mol Sci
; 24(19)2023 Sep 27.
Article
de En
| MEDLINE
| ID: mdl-37834044
ABSTRACT
Ferroptosis is a newly characterized form of programmed cell death. The fundamental biochemical feature of ferroptosis is the lethal accumulation of iron-catalyzed lipid peroxidation. It has gradually been recognized that ferroptosis is implicated in the pathogenesis of a variety of human diseases. Increasing evidence has shed light on ferroptosis regulation by amino acid metabolism. Herein, we report that arginine deprivation potently inhibits erastin-induced ferroptosis, but not RSL3-induced ferroptosis, in several types of mammalian cells. Arginine presence reduces the intracellular glutathione (GSH) level by sustaining the biosynthesis of fumarate, which functions as a reactive α,ß-unsaturated electrophilic metabolite and covalently binds to GSH to generate succinicGSH. siRNA-mediated knockdown of argininosuccinate lyase, the critical urea cycle enzyme directly catalyzing the biosynthesis of fumarate, significantly decreases cellular fumarate and thus relieves erastin-induced ferroptosis in the presence of arginine. Furthermore, fumarate is decreased during erastin exposure, suggesting that a protective mechanism exists to decelerate GSH depletion in response to pro-ferroptotic insult. Collectively, this study reveals the ferroptosis regulation by the arginine metabolism and expands the biochemical functionalities of arginine.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Ferroptose
Limites:
Animals
/
Humans
Langue:
En
Journal:
Int J Mol Sci
Année:
2023
Type de document:
Article
Pays d'affiliation:
Chine