A Mitochondrial-Targeted Nitroxide Is a Potent Inhibitor of Ferroptosis.
A Mitochondrial-Targeted Nitroxide Is a Potent Inhibitor of Ferroptosis.
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DOI：
10.1021/acscentsci.6b00199
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发表时间：
2016-09-28
影响因子：
18.2
通讯作者：
Wipf, Peter
中科院分区：
文献类型：
--
作者：
Krainz, Tanja;Gaschler, Michael M.;Lim, Chaemin;Sacher, Joshua R.;Stockwell, Brent R.;Wipf, Peter
近年来，发现抑制铁凋亡（一种受调节的非凋亡性细胞死亡形式）的化合物和机制引起了极大的兴趣。在这项研究中，我们证明了XJB-5-131，JP 4 -039和其他基于氮氧自由基的脂质过氧化减轻剂防止HT-1080，BJeLR和panc-1细胞中的铁凋亡细胞死亡的能力。合成了活性氧清除剂XJB-5-131和JP 4 -039的几种类似物，以探索构效关系以及亚细胞定位对这些新型铁凋亡抑制剂效力的影响。它们的生物活性与它们的结构、相对亲脂性和各自在线粒体中的富集度相关超过几个数量级，揭示了线粒体内脂质过氧化在铁凋亡中的关键作用。这些结果还表明，防止线粒体脂质氧化可能为缺血/再灌注诱导的组织损伤、急性肾损伤和其他涉及铁细胞死亡途径的病理提供可行的治疗机会。亚铁凋亡是一种新的调节性细胞死亡形式，可以通过氮氧化物XJB-5-131来预防，这表明保护线粒体脂质可能为激活亚铁凋亡途径的病理提供治疗机会。
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. Ferroptosis, a new form of regulated cell death, can be prevented by the nitroxide XJB-5-131, suggesting that protecting mitochondrial lipids might offer a therapeutic opportunity in pathologies that activate ferroptotic pathways.
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影响因子：
15
作者：
Beck, Johannes G.;Chatterjee, Jayanta;Kessler, Horst
通讯作者：
Kessler, Horst
影响因子：
19
作者：
Yang WS;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
8.8
作者：
Xun Z;Rivera-Sánchez S;Ayala-Peña S;Lim J;Budworth H;Skoda EM;Robbins PD;Niedernhofer LJ;Wipf P;McMurray CT
通讯作者：
McMurray CT
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
2.1
作者：
Conrad M;Friedmann Angeli JP
通讯作者：
Friedmann Angeli JP