title: A Mitochondrial-Targeted Nitroxide Is a Potent Inhibitor of Ferroptosis.
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.
authors.affiliation: Department of Chemistry, University of Pittsburgh , 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Tanja
authors.initials: T
authors.lastname: Krainz
authors.affiliation: Department of Biological Sciences and Department of Chemistry, Columbia University , 550 West 120th Street, Northwest Corner Building, MC 4846, New York, New York 10027, United States.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gaschler
authors.affiliation: Department of Chemistry, University of Pittsburgh , 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Chaemin
authors.initials: C
authors.lastname: Lim
authors.affiliation: Department of Chemistry, University of Pittsburgh , 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sacher
authors.affiliation: Department of Biological Sciences and Department of Chemistry, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, New York 10027, United States; Department of Biological Sciences and Department of Chemistry, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, New York 10027, United States.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stockwell
authors.affiliation: Department of Chemistry, University of Pittsburgh , 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf