Male subfertility induced by heterozygous expression of catalytically inactive glutathione peroxidase 4 is rescued in vivo by systemic inactivation of the Alox15 gene

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 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 knockin mice expressing the Sec46Ala-Gpx4 mutant, in which the catalytic selenocysteine was replaced by a redox inactive alanine. Since homozygous Gpx4 knockin mice (Sec46Ala-Gpx4+/+) are not viable we created heterozygous animals (Sec46Ala-Gpx4+/-) and crossed them with Alox15 knockout mice (Alox15-/-). Male Sec46Ala-Gpx4+/--mice but not their female littermates were subfertile. Sperms 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 wildtype sperms. 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 wildtype 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 sperms. If these data can be confirmed in humans ALOX15 inhibitors might counteract male infertility related to GPX4 deficiency.

The Journal of biological chemistry. 2016 Sep 15 [Epub ahead of print]

Simone Hanna Brutsch, Marlena Rademacher, Sophia Regine Roth, Karin Muller, Susanne Eder, Dagmar Viertel, Christiane Franz, Hartmut Kuhn, Astrid Borchert

Charite, Germany;, Leibnitz Institute, Germany., Charite, Germany; .