TY  - JOUR
AU  - Ingold, Irina
AU  - Aichler, Michaela
AU  - Yefremova, Elena
AU  - Roveri, Antonella
AU  - Buday, Katalin
AU  - Doll, Sebastian
AU  - Tasdemir, Adrianne
AU  - Hoffard, Nils
AU  - Wurst, Wolfgang
AU  - Walch, Axel
AU  - Ursini, Fulvio
AU  - Friedmann Angeli, José Pedro
AU  - Conrad, Marcus
TI  - Expression of a Catalytically Inactive Mutant Form of Glutathione Peroxidase 4 (Gpx4) Confers a Dominant-negative Effect in Male Fertility.
JO  - The journal of biological chemistry
VL  - 290
IS  - 23
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.60645
M1  - DZNE-2020-04284
SP  - 14668-14678
PY  - 2015
AB  - 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.
KW  - Amino Acid Substitution
KW  - Animals
KW  - Catalytic Domain
KW  - Cells, Cultured
KW  - Embryo Loss: genetics
KW  - Embryo Loss: metabolism
KW  - Embryo Loss: pathology
KW  - Female
KW  - Glutathione Peroxidase: genetics
KW  - Glutathione Peroxidase: metabolism
KW  - Heterozygote
KW  - Homozygote
KW  - Infertility, Male: genetics
KW  - Infertility, Male: metabolism
KW  - Infertility, Male: pathology
KW  - Male
KW  - Mice
KW  - Mice, Transgenic
KW  - Phospholipid Hydroperoxide Glutathione Peroxidase
KW  - Selenocysteine: genetics
KW  - Serine: genetics
KW  - Spermatogenesis
KW  - Spermatozoa: metabolism
KW  - Spermatozoa: pathology
KW  - Spermatozoa: ultrastructure
KW  - Selenocysteine (NLM Chemicals)
KW  - Serine (NLM Chemicals)
KW  - Phospholipid Hydroperoxide Glutathione Peroxidase (NLM Chemicals)
KW  - Glutathione Peroxidase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25922076
C2  - pmc:PMC4505533
DO  - DOI:10.1074/jbc.M115.656363
UR  - https://pub.dzne.de/record/137962
ER  -