Schneider Manuela, Förster Heidi, Boersma Auke, Seiler Alexander, Wehnes Helga, Sinowatz Fred, Neumüller Christine, Deutsch Manuel J, Walch Axel, Hrabé de Angelis Martin, Wurst Wolfgang, Ursini Fulvio, Roveri Antonella, Maleszewski Marek, Maiorino Matilde, Conrad Marcus
Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
FASEB J. 2009 Sep;23(9):3233-42. doi: 10.1096/fj.09-132795. Epub 2009 May 5.
Selenium is linked to male fertility. Glutathione peroxidase 4 (GPx4), first described as an antioxidant enzyme, is the predominant selenoenzyme in testis and has been suspected of being vital for spermatogenesis. Cytosolic, mitochondrial, and nuclear isoforms are all encoded by the same gene. While disruption of entire GPx4 causes early embryonic lethality in mice, inactivation of nuclear GPx4 does not impair embryonic development or fertility. Here, we show that deletion of mitochondrial GPx4 (mGPx4) allows both normal embryogenesis and postnatal development, but causes male infertility. Infertility was associated with impaired sperm quality and severe structural abnormalities in the midpiece of spermatozoa. Knockout sperm display higher protein thiol content and recapitulate features typical of severe selenodeficiency. Interestingly, male infertility induced by mGPx4 depletion could be bypassed by intracytoplasmic sperm injection. We also show for the first time that mGPx4 is the prevailing GPx4 product in male germ cells and that mGPx4 disruption has no effect on proliferation or apoptosis of germinal or somatic tissue. Our study finally establishes that mitochondrial GPx4 confers the vital role of selenium in mammalian male fertility and identifies cytosolic GPx4 as the only GPx4 isoform being essential for embryonic development and apoptosis regulation.
硒与男性生育能力相关。谷胱甘肽过氧化物酶4（GPx4）最初被描述为一种抗氧化酶，是睾丸中主要的含硒酶，一直被怀疑对精子发生至关重要。胞质、线粒体和核异构体均由同一基因编码。虽然整个GPx4的缺失会导致小鼠早期胚胎致死，但核GPx4的失活并不损害胚胎发育或生育能力。在此，我们表明线粒体GPx4（mGPx4）的缺失既允许正常的胚胎发生和出生后发育，但会导致雄性不育。不育与精子质量受损以及精子中段严重的结构异常有关。敲除精子显示出更高的蛋白质硫醇含量，并重现了严重硒缺乏的典型特征。有趣的是，mGPx4缺失诱导的雄性不育可通过胞浆内精子注射绕过。我们还首次表明，mGPx4是雄性生殖细胞中主要的GPx4产物，并且mGPx4的破坏对生殖或体细胞组织的增殖或凋亡没有影响。我们的研究最终确定线粒体GPx4赋予了硒在哺乳动物雄性生育中的重要作用，并确定胞质GPx4是唯一对胚胎发育和凋亡调节至关重要的GPx4异构体。
