Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-Mediated cell death
Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-Mediated cell death
复制标题
DOI：
10.1016/j.cmet.2008.07.005
复制
发表时间：
2008-09-03
期刊：
影响因子：
29
通讯作者：
Conrad, Marcus
中科院分区：
文献类型：
--
作者：
Seiler, Alexander;Schneider, Manuela;Conrad, Marcus
氧化应激和谷胱甘肽耗竭与各种急性和慢性退行性疾病有关，但其分子机制仍不清楚。与认为氧自由基是有害的细胞和组织的非特异性氧化的基本生物分子，我们现在证明，氧化应激感测和转导谷胱甘肽过氧化物酶4（GPx 4）到一个尚未认识到的细胞死亡途径。小鼠和细胞中的诱导GPx 4失活揭示了12/15-脂氧合酶衍生的脂质过氧化作为特异性下游事件，触发凋亡诱导因子（AIF）介导的细胞死亡。细胞死亡可以通过α-生育酚（α-Toc）、12/15-脂氧合酶抑制剂或siRNA介导的AIF沉默来完全防止。因此，12/15-脂氧合酶缺陷细胞对谷胱甘肽耗竭具有高度抗性。神经元特异性GPx 4耗竭导致体内和离体神经变性，突出了该途径在神经元细胞中的重要性。由于氧化应激在许多人类疾病的病因学中是常见的，因此所确定的途径揭示了未来治疗的有希望的靶点。
Oxidative stress in conjunction with glutathione depletion has been linked with various acute and chronic degenerative disorders, yet the molecular mechanisms have remained unclear. In contrast to the belief that oxygen radicals are detrimental to cells and tissues by unspecific oxidation of essential biomolecules, we now demonstrate that oxidative stress is sensed and transduced by glutathione peroxidase 4 (GPx4) into a-yet-unrecognized cell-death pathway. Inducible GPx4 inactivation in mice and cells revealed 12/15-lipoxygenase-derived lipid peroxidation as specific downstream event, triggering apoptosis-inducing factor (AIF)-mediated cell death. Cell death could be entirely prevented either by alpha-tocopherol (alpha-Toc), 12/15-lipoxygenase inhibitors, or siRNA-mediated AIF silencing. Accordingly, 12/15-/ipoxygenase-deficient cells were highly resistant to glutathione depletion. Neuron-specific GPx4 depletion caused neurodegeneration in vivo and ex vivo, highlighting the importance of this pathway in neuronal cells. Since oxidative stress is common in the etiology of many human disorders, the identified pathway reveals promising targets for future therapies.