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@ARTICLE{Ingold:137962,
      author       = {Ingold, Irina and Aichler, Michaela and Yefremova, Elena
                      and Roveri, Antonella and Buday, Katalin and Doll, Sebastian
                      and Tasdemir, Adrianne and Hoffard, Nils and Wurst, Wolfgang
                      and Walch, Axel and Ursini, Fulvio and Friedmann Angeli,
                      José Pedro and Conrad, Marcus},
      title        = {{E}xpression of a {C}atalytically {I}nactive {M}utant
                      {F}orm of {G}lutathione {P}eroxidase 4 ({G}px4) {C}onfers a
                      {D}ominant-negative {E}ffect in {M}ale {F}ertility.},
      journal      = {The journal of biological chemistry},
      volume       = {290},
      number       = {23},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.60645},
      reportid     = {DZNE-2020-04284},
      pages        = {14668-14678},
      year         = {2015},
      abstract     = {The selenoenzyme Gpx4 is essential for early embryogenesis
                      and cell viability for its unique function to prevent
                      phospholipid oxidation. Recently, the cytosolic form of Gpx4
                      was identified as an upstream regulator of a novel form of
                      non-apoptotic cell death, called ferroptosis, whereas the
                      mitochondrial isoform of Gpx4 was previously shown to be
                      crucial for male fertility. Here, we generated and analyzed
                      mice with a targeted mutation of the active site
                      selenocysteine of Gpx4 $(Gpx4_U46S).$ Mice homozygous for
                      $Gpx4_U46S$ died at the same embryonic stage (E7.5) as
                      Gpx4(-/-) embryos as expected. Surprisingly, male mice
                      heterozygous for $Gpx4_U46S$ presented subfertility.
                      Subfertility was manifested in a reduced number of litters
                      from heterozygous breeding and an impairment of spermatozoa
                      to fertilize oocytes in vitro. Morphologically, sperm
                      isolated from heterozygous $Gpx4_U46S$ mice revealed many
                      structural abnormalities particularly in the spermatozoa
                      midpiece due to improper oxidation and polymerization of
                      sperm capsular proteins and malformation of the
                      mitochondrial capsule surrounding and stabilizing sperm
                      mitochondria. These findings are reminiscent of sperm
                      isolated from selenium-deprived rodents or from mice
                      specifically lacking mitochondrial Gpx4. Due to a strongly
                      facilitated incorporation of Ser in the polypeptide chain as
                      compared with selenocysteine at the UGA codon, expression of
                      the catalytically inactive $Gpx4_U46S$ was found to be
                      strongly increased. Because the stability of the
                      mitochondrial capsule of mature spermatozoa depends on the
                      moonlighting function of Gpx4 both as an enzyme oxidizing
                      capsular protein thiols and as a structural protein, tightly
                      controlled expression of functional Gpx4 emerges as a key
                      for full male fertility.},
      keywords     = {Amino Acid Substitution / Animals / Catalytic Domain /
                      Cells, Cultured / Embryo Loss: genetics / Embryo Loss:
                      metabolism / Embryo Loss: pathology / Female / Glutathione
                      Peroxidase: genetics / Glutathione Peroxidase: metabolism /
                      Heterozygote / Homozygote / Infertility, Male: genetics /
                      Infertility, Male: metabolism / Infertility, Male: pathology
                      / Male / Mice / Mice, Transgenic / Phospholipid
                      Hydroperoxide Glutathione Peroxidase / Selenocysteine:
                      genetics / Serine: genetics / Spermatogenesis / Spermatozoa:
                      metabolism / Spermatozoa: pathology / Spermatozoa:
                      ultrastructure / Selenocysteine (NLM Chemicals) / Serine
                      (NLM Chemicals) / Phospholipid Hydroperoxide Glutathione
                      Peroxidase (NLM Chemicals) / Glutathione Peroxidase (NLM
                      Chemicals)},
      cin          = {AG Wurst},
      ddc          = {540},
      cid          = {I:(DE-2719)1140001},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25922076},
      pmc          = {pmc:PMC4505533},
      doi          = {10.1074/jbc.M115.656363},
      url          = {https://pub.dzne.de/record/137962},
}