Short Form Glutathione Peroxidase 4 Is the Essential Isoform Required for Survival and Somatic Mitochondrial Functions
Short Form Glutathione Peroxidase 4 Is the Essential Isoform Required for Survival and Somatic Mitochondrial Functions
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DOI：
10.1074/jbc.m109.032839
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发表时间：
2009-11-06
影响因子：
4.8
通讯作者：
Ran, Qitao
中科院分区：
文献类型：
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作者：
Liang, Hanyu;Yoo, Si-Eun;Ran, Qitao
谷胱甘肽过氧化物酶4 （Glutathione peroxidase 4, Gpx4）是一种重要的抗氧化酶，具有多种功能。Gpx4基因产生了一种长型Gpx4蛋白和一种短型Gpx4蛋白，它们通过N端线粒体信号肽的存在或缺乏来区分。在这项研究中，我们使用突变的GPX4基因产生转基因小鼠，这些基因编码长型GPX4 （lPX4基因）或短型GPX4 （sGPX4基因）。我们的研究结果表明，携带sGPX4基因的转基因小鼠在所有组织中都增加了Gpx4蛋白，并对diquat诱导的肝细胞凋亡具有保护作用。此外，sGPX4基因能够挽救小鼠gpx4缺失突变的致死表型。相比之下，携带lGPX4基因的转基因小鼠仅在睾丸中增加了Gpx4蛋白，lGPX4基因未能挽救小鼠Gpx4缺失突变的致死表型。在经sGPX4基因拯救的Gpx4缺失小鼠中，Gpx4蛋白存在于体细胞组织分离的线粒体中，并且Gpx4蛋白在这些小鼠中的亚线粒体分布模式与野生型小鼠相同。有趣的是，被sGPX4基因拯救的雄性gpx4缺失小鼠不育，并表现出精子畸形。总之，我们的研究结果首次表明，短形式的Gpx4蛋白存在于体细胞组织线粒体中，对小鼠的生存和防止细胞凋亡至关重要，而长形式的Gpx4蛋白对雄性生殖能力很重要。
Glutathione peroxidase 4 (Gpx4) is an essential antioxidant enzyme having multiple functions. A long form Gpx4 protein and a short form Gpx4 protein, which are distinguishable by the presence or lack of a mitochondrial signal peptide at the N terminus, are generated from the Gpx4 gene. In this study, we generated transgenic mice using mutated GPX4 genes encoding either the long form Gpx4 (lPX4 gene) or the short form Gpx4 (sGPX4 gene). Our results showed that transgenic mice with the sGPX4 gene had increased Gpx4 protein in all tissues and were protected against diquat-induced apoptosis in liver. Moreover, the sGPX4 gene was able to rescue the lethal phenotype of the mouse Gpx4-null mutation. In contrast, transgenic mice with the lGPX4 gene had increased Gpx4 protein only in the testes, and the lGPX4 gene failed to rescue the lethal phenotype of the mouse Gpx4-null mutation. In Gpx4-null mice rescued by the sGPX4 gene, the Gpx4 protein was present in mitochondria isolated from somatic tissues, and the submitochondrial distribution pattern of the Gpx4 protein in these mice was identical to that in wild-type mice. Interestingly, the male Gpx4-null mice rescued by the sGPX4 gene were infertile and exhibited sperm malformation. Together, our results demonstrated for the first time that the short form Gpx4 protein is present in somatic tissue mitochondria and is essential for survival and protection against apoptosis in mice, whereas the long form Gpx4 protein is important for male fertility.