Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.
Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.
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DOI：
10.1038/nchembio.2238
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发表时间：
2017-01
影响因子：
14.8
通讯作者：
Bayır H
中科院分区：
文献类型：
--
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
神秘的脂质过氧化产物被认为是铁下垂的最接近的执行者--这是一种由谷胱甘肽过氧化物酶4(Gpx4)不足引发的特殊死亡程序。在这里，通过使用定量氧化还原脂质组学、反向遗传学、生物信息学和系统生物学，我们发现铁下垂的执行涉及一个高度组织化的氧化中心，其中只有一类磷脂-磷脂酰乙醇胺(PE)在内质网相关的隔室中经历氧化，并针对两个脂肪酰基-花生四烯酸甲酯(AA)和肾上腺素甲酰(ADA)。通过基因或药物抑制酰基辅酶A合成酶4抑制AA或AdA酯化为PE，是一种特异性的反铁性抢救途径。脂肪氧合酶(LOX)产生双氧和三氧(15-羟基过氧基)双酰化PE物种，作为死亡信号，而生育酚和生育三烯醇抑制LOX并预防铁下垂，这表明维生素E具有不可预见的体内平衡生理作用。这种氧化PE死亡途径也可能是药物开发的目标。
Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis - a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Here, by using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology we discovered that execution of ferroptosis involves a highly organized oxygenation center, whereby only one class of phospholipids, phosphatidylethanolamines (PE), undergoes oxidation in the ER-associated compartments with the specificity towards two fatty acyls – arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 acts as a specific anti-ferroptotic rescue pathway. Lipoxygenases (LOX) generate doubly- and triply-oxygenated (15-hydroperoxy)-di-acylated PE species which act as death signals while tocopherols and tocotrienols suppress LOX and protect against ferroptosis suggesting an unforeseen homeostatic physiological role of vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
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DOI：
10.1016/j.bbalip.2014.10.002
发表时间：
2015-04
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Kuhn H;Banthiya S;van Leyen K
通讯作者：
van Leyen K
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：
4
作者：
Dixon SJ;Winter GE;Musavi LS;Lee ED;Snijder B;Rebsamen M;Superti-Furga G;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
14.8
作者：
Kagan, VE;Tyurin, VA;Borisenko, GG
通讯作者：
Borisenko, GG
影响因子：
6.5
作者：
McIntyre, Thomas M.;Prescott, Stephen M.;Stafforini, Diana M.
通讯作者：
Stafforini, Diana M.