PDF(Pubmed)
Abstract：
Selenoprotein GPX4 (glutathione peroxidase 4), originally known as PHGPX (phospholipid hydroperoxide glutathione peroxidase), is the main oxidoreductase in the use of glutathione as a reducing agent in scavenging lipid peroxidation products. There are three GPX4 isoforms: cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), with distinct spatiotemporal expression patterns during embryonic development and adult life. In addition to inducing the main phenotype of ferroptosis, the loss of GPX4 can in some cells trigger apoptosis, necroptosis, pyroptosis, or parthanatos, which mediates or accelerates developmental defects, tissue damage, and sterile inflammation. The interaction of GPX4 with the autophagic degradation pathway further modulates cell fate in response to oxidative stress. Impaired GPX4 function is implicated in tumorigenesis, neurodegeneration, infertility, inflammation, immune disorders, and ischemia-reperfusion injury. Additionally, the R152H mutation in GPX4 can promote the development of Sedaghatian-type spinal metaphyseal dysplasia, a rare and fatal disease in newborns. Here, we discuss the roles of classical GPX4 functions as well as emerging GPX4-regulated processes in cell death, autophagy, and disease.Abbreviations: AA: arachidonic acid; cGPX4: cytosolic GPX4; CMA: chaperone-mediated autophagy; DAMPs: danger/damage-associated molecular patterns; mGPX4: mitochondrial GPX4; nGPX4: nuclear GPX4; GSDMD-N: N-terminal fragment of GSDMD; I/R: ischemia-reperfusion; PLOOH: phospholipid hydroperoxide; PUFAs: polyunsaturated fatty acids; RCD: regulated cell death; ROS: reactive oxygen species; Se: selenium; SSMD: Sedaghatian-type spondylometaphyseal dysplasia; UPS: ubiquitin-proteasome system.
摘要：
硒蛋白GPX4（谷胱甘肽过氧化物酶4），最初被称为PHGPX（磷脂过氧化氢谷胱甘肽过氧化物酶），是利用谷胱甘肽作为清除脂质过氧化产物的还原剂的主要氧化还原酶。有三种GPX4亚型：胞质（cGPX4），线粒体（mGPX4），和核（nGPX4），在胚胎发育和成年期具有不同的时空表达模式。除了诱导主要表型的铁死亡，GPX4的缺失可以在某些细胞中引发细胞凋亡，坏死,焦亡,或者parthanatos,介导或加速发育缺陷，组织损伤,和无菌炎症。GPX4与自噬降解途径的相互作用进一步调节响应于氧化应激的细胞命运。受损的GPX4功能与肿瘤发生有关，神经变性,不孕症,炎症,免疫疾病，和缺血再灌注损伤。此外,GPX4中的R152H突变可促进Sedaghadian型脊柱干phy端发育不良的发展,新生儿的一种罕见而致命的疾病。这里,我们讨论了经典的GPX4功能以及新兴的GPX4调节过程在细胞死亡中的作用，自噬,和疾病。缩写：AA：花生四烯酸；cGPX4：胞质GPX4；CMA：伴侣介导的自噬；DAMPs：危险/损伤相关分子模式；mGPX4：线粒体GPX4；nGPX4：核GPX4；GSDMD-N：GSDMD的N-末端片段；I/R：缺血再灌注；PLOPX4：磷脂多聚脂肪酸：不饱和脂肪酸：SSPUOOPUPS类过氧化氢类
