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Mitochondrial glutathione peroxidase 4 disruption causes male infertility

Manuela Schneider^*,1, Heidi Förster^*, Auke Boersma, Alexander Seiler^*, Helga Wehnes, Fred Sinowatz^¶, Christine Neumüller^¶, Manuel J. Deutsch, Axel Walch, Martin Hrabé de Angelis, Wolfgang Wurst^||, Fulvio Ursini^#, Antonella Roveri^#, Marek Maleszewski^**, Matilde Maiorino^# and Marcus Conrad^*,2

^* Institute of Clinical Molecular Biology and Tumor Genetics,

Institute of Experimental Genetics,

Institute of Pathology,

Department of Gene Vectors, and

^|| Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;

^¶ Department of Veterinary Anatomy II, Ludwig-Maximilians-University of Munich, Munich, Germany;

^# Department of Biological Chemistry, University of Padua, Padova, Italy; and

^** Department of Embryology, Institute of Zoology, University of Warsaw, Warsaw, Poland

² Correspondence: Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Marchioninistr. 25, D-81377 Munich, Germany. E-mail: marcus.conrad{at}helmholtz-muenchen.de

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.—Schneider, M., Förster, H., Boersma, A., Seiler, A., Wehnes, H., Sinowatz, F., Neumüller, C., Deutsch, M. J., Walch, A., Hrabé de Angelis, M., Wurst, W., Ursini, F., Roveri, A., Maleszewski, M., Maiorino, M. Conrad, M. Mitochondrial glutathione peroxidase 4 disruption causes male infertility.

Key Words: PHGPx • redox metabolism • selenoprotein • spermatogenesis

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