A Mitochondrial-Targeted Nitroxide Is a Potent Inhibitor of Ferroptosis.
ACS Cent Sci
; 2(9): 653-659, 2016 Sep 28.
Article
em En
| MEDLINE
| ID: mdl-27725964
ABSTRACT
Discovering compounds and mechanisms for inhibiting ferroptosis, a form of regulated, nonapoptotic cell death, has been of great interest in recent years. In this study, we demonstrate the ability of XJB-5-131, JP4-039, and other nitroxide-based lipid peroxidation mitigators to prevent ferroptotic cell death in HT-1080, BJeLR, and panc-1 cells. Several analogues of the reactive oxygen species (ROS) scavengers XJB-5-131 and JP4-039 were synthesized to probe structure-activity relationships and the influence of subcellular localization on the potency of these novel ferroptosis suppressors. Their biological activity correlated well over several orders of magnitude with their structure, relative lipophilicity, and respective enrichment in mitochondria, revealing a critical role of intramitochondrial lipid peroxidation in ferroptosis. These results also suggest that preventing mitochondrial lipid oxidation might offer a viable therapeutic opportunity in ischemia/reperfusion-induced tissue injury, acute kidney injury, and other pathologies that involve ferroptotic cell death pathways.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article