title: Male Subfertility Induced by Heterozygous Expression of Catalytically Inactive Glutathione Peroxidase 4 Is Rescued in Vivo by Systemic Inactivation of the Alox15 Gene.
abstract: Glutathione peroxidase 4 (GPX4) and arachidonic acid 15-lipoxygenase (ALOX15) are antagonizing enzymes in the metabolism of hydroperoxy lipids. In spermatoid cells and/or in the male reproductive system both enzymes are apparently expressed, and GPX4 serves as anti-oxidative enzyme but also as a structural protein. In this study we explored whether germ line inactivation of the Alox15 gene might rescue male subfertility induced by heterozygous expression of catalytically silent Gpx4. To address this question we employed Gpx4 knock-in mice expressing the Sec46Ala-Gpx4 mutant, in which the catalytic selenocysteine was replaced by a redox inactive alanine. Because homozygous Gpx4 knock-in mice (Sec46Ala-Gpx4+/+) are not viable we created heterozygous animals (Sec46Ala-Gpx4+/-) and crossed them with Alox15 knock-out mice (Alox15-/-). Male Sec46Ala-Gpx4+/-mice, but not their female littermates, were subfertile. Sperm extracted from the epididymal cauda showed strongly impaired motility characteristics and severe structural midpiece alterations (swollen mitochondria, intramitochondrial vacuoles, disordered mitochondrial capsule). Despite these structural alterations, they exhibited similar respiration characteristics than wild-type sperm. When Sec46Ala-Gpx4+/-mice were crossed with Alox15-deficient animals, the resulting males (Sec46Ala-Gpx4+/-+Alox15-/-) showed normalized fertility, and sperm motility was reimproved to wild-type levels. Taken together these data suggest that systemic inactivation of the Alox15 gene normalizes the reduced fertility of male Sec46Ala-Gpx4+/-mice by improving the motility of their sperm. If these data can be confirmed in humans, ALOX15 inhibitors might counteract male infertility related to GPX4 deficiency.
authors.affiliation: From the Institute of Biochemistry, Charite-University Medicine Berlin, Virchowweg 6, D-10117 Berlin, Germany and.
authors.forename: Simone Hanna
authors.initials: SH
authors.lastname: Brütsch
authors.affiliation: From the Institute of Biochemistry, Charite-University Medicine Berlin, Virchowweg 6, D-10117 Berlin, Germany and.
authors.forename: Marlena
authors.initials: M
authors.lastname: Rademacher
authors.affiliation: From the Institute of Biochemistry, Charite-University Medicine Berlin, Virchowweg 6, D-10117 Berlin, Germany and.
authors.forename: Sophia Regina
authors.initials: SR
authors.lastname: Roth
authors.affiliation: Leibniz Institute for Zoo and Wildlife Research, Alfred-Kowalke-Str. 17, D-10315 Berlin, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Müller
authors.affiliation: Leibniz Institute for Zoo and Wildlife Research, Alfred-Kowalke-Str. 17, D-10315 Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Eder
authors.affiliation: Leibniz Institute for Zoo and Wildlife Research, Alfred-Kowalke-Str. 17, D-10315 Berlin, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Viertel
authors.affiliation: Leibniz Institute for Zoo and Wildlife Research, Alfred-Kowalke-Str. 17, D-10315 Berlin, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Franz
authors.affiliation: From the Institute of Biochemistry, Charite-University Medicine Berlin, Virchowweg 6, D-10117 Berlin, Germany and hartmut.kuehn@charite.de.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kuhn
authors.affiliation: From the Institute of Biochemistry, Charite-University Medicine Berlin, Virchowweg 6, D-10117 Berlin, Germany and.
authors.forename: Astrid
authors.initials: A
authors.lastname: Borchert
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D055879:Gene Knock-In Techniques; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D013081:Sperm Motility; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism / Q000473:pathology
chemical_list: D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C000611332:glutathione peroxidase 4, mouse; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D010100:Oxygen
keywords: eicosanoid; lipoxygenase pathway; mitochondria; oxidative stress; sperm