Mitochondrial glutathione peroxidase 4 disruption causes male infertility.
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.
Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Manuela
M
Schneider
Heidi
H
Förster
Auke
A
Boersma
Alexander
A
Seiler
Helga
H
Wehnes
Fred
F
Sinowatz
Christine
C
Neumüller
Manuel J
MJ
Deutsch
Axel
A
Walch
Martin
M
Hrabé de Angelis
Wolfgang
W
Wurst
Fulvio
F
Ursini
Antonella
A
Roveri
Marek
M
Maleszewski
Matilde
M
Maiorino
Marcus
M
Conrad
D000818:Animals; D017209:Apoptosis; D047108:Embryonic Development; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000502:physiology*; D007248:Infertility, Male / Q000209:etiology*; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000502:physiology*; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D012643:Selenium / Q000502:physiology; D013094:Spermatozoa / Q000473:pathology
D024101:Mitochondrial Proteins; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D012643:Selenium