Male Subfertility Induced by Heterozygous Expression of Catalytically Inactive Glutathione Peroxidase 4 Is Rescued in Vivo by Systemic Inactivation of the Alox15 Gene
| Autor: | Susanne Eder, Astrid Borchert, Marlena Rademacher, Hartmut Kühn, Dagmar Viertel, Sophia Regina Roth, Karin Müller, Christiane Franz, Simone Hanna Brütsch |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Down-Regulation Motility Mitochondrion Biology Arachidonate 12-Lipoxygenase GPX4 medicine.disease_cause Biochemistry Male infertility Mice 03 medical and health sciences medicine Animals Arachidonate 15-Lipoxygenase Gene Knock-In Techniques Molecular Biology Infertility Male Sperm motility Mice Knockout chemistry.chemical_classification Glutathione Peroxidase Cell Biology Phospholipid Hydroperoxide Glutathione Peroxidase medicine.disease Lipids Spermatozoa Molecular biology Sperm Mitochondria Oxygen Oxidative Stress 030104 developmental biology Enzyme chemistry Mutation mitochondria oxidative stress sperm lipoxygenase pathway eicosanoid Sperm Motility Female Oxidative stress |
| Zdroj: | The journal of biological chemistry, 291: 23578-23588 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m116.738930 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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