• PMID: 19417079
• Gene Name: GPX4
• Condition: Male infertility
• Association: Associated
• Sex: Male
• Infertility type: Male infertility

Mitochondrial glutathione peroxidase 4 disruption causes male infertility

Schneider M, Förster H, Boersma A, Seiler A, Wehnes H, Sinowatz F, Neumüller C, Deutsch MJ, Walch A, Hrabé de Angelis M, Wurst W, Ursini F, Roveri A, Maleszewski M, Maiorino M, Conrad M.

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. FAU - Schneider, Manuela AU - Schneider M AD - Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. FAU - Förster, Heidi AU - Förster H FAU - Boersma, Auke AU - Boersma A FAU - Seiler, Alexander AU - Seiler A FAU - Wehnes, Helga AU - Wehnes H FAU - Sinowatz, Fred AU - Sinowatz F FAU - Neumüller, Christine AU - Neumüller C FAU - Deutsch, Manuel J AU - Deutsch MJ FAU - Walch, Axel AU - Walch A FAU - Hrabé de Angelis, Martin AU - Hrabé de Angelis M FAU - Wurst, Wolfgang AU - Wurst W FAU - Ursini, Fulvio AU - Ursini F FAU - Roveri, Antonella AU - Roveri A FAU - Maleszewski, Marek AU - Maleszewski M FAU - Maiorino, Matilde AU - Maiorino M