A Mitochondrial-Targeted Nitroxide Is a Potent Inhibitor of Ferroptosis

Krainz, Tanja; Gaschler, Michael M.; Lim, Chaemin; Sacher, Joshua R.; Stockwell, Brent R.; Wipf, Peter

doi:10.1021/acscentsci.6b00199

Cited by 186 publications

(147 citation statements)

References 30 publications

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“…Taken together, these results confirm that erastin-induced ferroptosis involves mitochondrial damage [15], [30] in neuronal HT-22 cells and substantiates the pivotal role of BID in ferroptosis which was observed before in HT-22 Bid KO cells.…”

Section: Resultssupporting

confidence: 89%

BID links ferroptosis to mitochondrial cell death pathways

et al. 2017

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Ferroptosis has been defined as an oxidative and iron-dependent pathway of regulated cell death that is distinct from caspase-dependent apoptosis and established pathways of death receptor-mediated regulated necrosis. While emerging evidence linked features of ferroptosis induced e.g. by erastin-mediated inhibition of the Xc- system or inhibition of glutathione peroxidase 4 (Gpx4) to an increasing number of oxidative cell death paradigms in cancer cells, neurons or kidney cells, the biochemical pathways of oxidative cell death remained largely unclear. In particular, the role of mitochondrial damage in paradigms of ferroptosis needs further investigation.In the present study, we find that erastin-induced ferroptosis in neuronal cells was accompanied by BID transactivation to mitochondria, loss of mitochondrial membrane potential, enhanced mitochondrial fragmentation and reduced ATP levels. These hallmarks of mitochondrial demise are also established features of oxytosis, a paradigm of cell death induced by Xc- inhibition by millimolar concentrations of glutamate. Bid knockout using CRISPR/Cas9 approaches preserved mitochondrial integrity and function, and mediated neuroprotective effects against both, ferroptosis and oxytosis. Furthermore, the BID-inhibitor BI-6c9 inhibited erastin-induced ferroptosis, and, in turn, the ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 prevented mitochondrial dysfunction and cell death in the paradigm of oxytosis. These findings show that mitochondrial transactivation of BID links ferroptosis to mitochondrial damage as the final execution step in this paradigm of oxidative cell death.

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Section: Resultssupporting

confidence: 89%

BID links ferroptosis to mitochondrial cell death pathways

et al. 2017

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“…TK649.030 has the same sequence as JP4-039 but is linked to an acetate at the nitroxide oxygen, forming a base-cleavable hydroxylamine/nitroxide prodrug moiety. The synthesis of JP4-039, XJB-5-131, JRS527.084, and TK649.030 has been previously reported (25). The methods for preparation of the formulation of F14 have been published previously (26, 27).…”

Section: Methodsmentioning

confidence: 94%

Effectiveness of Analogs of the GS-Nitroxide, JP4-039, as Total Body Irradiation Mitigators

Epperly

Sacher

Krainz

et al. 2017

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Background/Aim Mitochondrial-targeted gramicidin S (GS)-nitroxide, JP4-039, has been demonstrated to be a potent radiation mitigator, and safe over a wide dose range. In addition, JP4-039 has organ-specific effectiveness when locally applied. Materials and Methods We tested the effect of another GS-nitroxide, XJB-5-131, which has more effective mitochondrial localization, and compared these results to those for radiation mitigation against the hematopoietic syndrome, and two analogs of JP4-039, which have the same mitochondrial localization signal, but different chemical payloads: JRS527.084 contains a second nitroxide per molecule, and TK649.030 contains an ester group attached to the nitroxide. Results The results demonstrate the superiority of JP4-039 as a systemic radiation mitigator. Conclusion: Structure–activity relationships and bioassays demonstrate that JP4-039 is an optimized small-molecule radiation mitigator.

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“…The nitroxide was also capable of subverting ferroptosis; we found EC 50 = 99 ± 5 nM under the same conditions that yielded 77 nM for 1 and 38 nM for Lip-1. Interestingly, Wipf and co-workers recently reported that mitochondrially targeted nitroxide derivatives are good inhibitors of ferroptotic cell death, 61 their best examples being slightly less effective than Fer-1, and therefore similar to the nitroxide derived from dihydroquinoline 1 .…”

Section: Discussionmentioning

confidence: 99%

On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death

et al. 2017

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Ferroptosis is a form of regulated necrosis associated with the iron-dependent accumulation of lipid hydroperoxides that may play a key role in the pathogenesis of degenerative diseases in which lipid peroxidation has been implicated. High-throughput screening efforts have identified ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) as potent inhibitors of ferroptosis − an activity that has been ascribed to their ability to slow the accumulation of lipid hydroperoxides. Herein we demonstrate that this activity likely derives from their reactivity as radical-trapping antioxidants (RTAs) rather than their potency as inhibitors of lipoxygenases. Although inhibited autoxidations of styrene revealed that Fer-1 and Lip-1 react roughly 10-fold more slowly with peroxyl radicals than reactions of α-tocopherol (α-TOH), they were significantly more reactive than α-TOH in phosphatidylcholine lipid bilayers − consistent with the greater potency of Fer-1 and Lip-1 relative to α-TOH as inhibitors of ferroptosis. None of Fer-1, Lip-1, and α-TOH inhibited human 15-lipoxygenase-1 (15-LOX-1) overexpressed in HEK-293 cells when assayed at concentrations where they inhibited ferroptosis. These results stand in stark contrast to those obtained with a known 15-LOX-1 inhibitor (PD146176), which was able to inhibit the enzyme at concentrations where it was effective in inhibiting ferroptosis. Given the likelihood that Fer-1 and Lip-1 subvert ferroptosis by inhibiting lipid peroxidation as RTAs, we evaluated the antiferroptotic potential of 1,8-tetrahydronaphthyridinols (hereafter THNs): rationally designed radical-trapping antioxidants of unparalleled reactivity. We show for the first time that the inherent reactivity of the THNs translates to cell culture, where lipophilic THNs were similarly effective to Fer-1 and Lip-1 at subverting ferroptosis induced by either pharmacological or genetic inhibition of the hydroperoxide-detoxifying enzyme Gpx4 in mouse fibroblasts, and glutamate-induced death of mouse hippocampal cells. These results demonstrate that potent RTAs subvert ferroptosis and suggest that lipid peroxidation (autoxidation) may play a central role in the process.

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A Mitochondrial-Targeted Nitroxide Is a Potent Inhibitor of Ferroptosis

Cited by 186 publications

References 30 publications

BID links ferroptosis to mitochondrial cell death pathways

BID links ferroptosis to mitochondrial cell death pathways

Effectiveness of Analogs of the GS-Nitroxide, JP4-039, as Total Body Irradiation Mitigators

On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death

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