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000137962 0247_ $$2doi$$a10.1074/jbc.M115.656363
000137962 0247_ $$2pmid$$apmid:25922076
000137962 0247_ $$2pmc$$apmc:PMC4505533
000137962 0247_ $$2ISSN$$a0021-9258
000137962 0247_ $$2ISSN$$a1067-8816
000137962 0247_ $$2ISSN$$a1083-351X
000137962 037__ $$aDZNE-2020-04284
000137962 041__ $$aEnglish
000137962 082__ $$a540
000137962 1001_ $$0P:(DE-HGF)0$$aIngold, Irina$$b0
000137962 245__ $$aExpression of a Catalytically Inactive Mutant Form of Glutathione Peroxidase 4 (Gpx4) Confers a Dominant-negative Effect in Male Fertility.
000137962 260__ $$aBethesda, Md.$$bSoc.60645$$c2015
000137962 264_1 $$2Crossref$$3online$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2015-04-28
000137962 264_1 $$2Crossref$$3print$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2015-06-05
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000137962 3367_ $$2BibTeX$$aARTICLE
000137962 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000137962 3367_ $$00$$2EndNote$$aJournal Article
000137962 520__ $$aThe 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.
000137962 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
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000137962 650_7 $$00CH9049VIS$$2NLM Chemicals$$aSelenocysteine
000137962 650_7 $$0452VLY9402$$2NLM Chemicals$$aSerine
000137962 650_7 $$0EC 1.11.1.12$$2NLM Chemicals$$aPhospholipid Hydroperoxide Glutathione Peroxidase
000137962 650_7 $$0EC 1.11.1.9$$2NLM Chemicals$$aGlutathione Peroxidase
000137962 650_2 $$2MeSH$$aAmino Acid Substitution
000137962 650_2 $$2MeSH$$aAnimals
000137962 650_2 $$2MeSH$$aCatalytic Domain
000137962 650_2 $$2MeSH$$aCells, Cultured
000137962 650_2 $$2MeSH$$aEmbryo Loss: genetics
000137962 650_2 $$2MeSH$$aEmbryo Loss: metabolism
000137962 650_2 $$2MeSH$$aEmbryo Loss: pathology
000137962 650_2 $$2MeSH$$aFemale
000137962 650_2 $$2MeSH$$aGlutathione Peroxidase: genetics
000137962 650_2 $$2MeSH$$aGlutathione Peroxidase: metabolism
000137962 650_2 $$2MeSH$$aHeterozygote
000137962 650_2 $$2MeSH$$aHomozygote
000137962 650_2 $$2MeSH$$aInfertility, Male: genetics
000137962 650_2 $$2MeSH$$aInfertility, Male: metabolism
000137962 650_2 $$2MeSH$$aInfertility, Male: pathology
000137962 650_2 $$2MeSH$$aMale
000137962 650_2 $$2MeSH$$aMice
000137962 650_2 $$2MeSH$$aMice, Transgenic
000137962 650_2 $$2MeSH$$aPhospholipid Hydroperoxide Glutathione Peroxidase
000137962 650_2 $$2MeSH$$aSelenocysteine: genetics
000137962 650_2 $$2MeSH$$aSerine: genetics
000137962 650_2 $$2MeSH$$aSpermatogenesis
000137962 650_2 $$2MeSH$$aSpermatozoa: metabolism
000137962 650_2 $$2MeSH$$aSpermatozoa: pathology
000137962 650_2 $$2MeSH$$aSpermatozoa: ultrastructure
000137962 7001_ $$0P:(DE-HGF)0$$aAichler, Michaela$$b1
000137962 7001_ $$0P:(DE-HGF)0$$aYefremova, Elena$$b2
000137962 7001_ $$0P:(DE-HGF)0$$aRoveri, Antonella$$b3
000137962 7001_ $$0P:(DE-HGF)0$$aBuday, Katalin$$b4
000137962 7001_ $$0P:(DE-HGF)0$$aDoll, Sebastian$$b5
000137962 7001_ $$0P:(DE-HGF)0$$aTasdemir, Adrianne$$b6
000137962 7001_ $$0P:(DE-HGF)0$$aHoffard, Nils$$b7
000137962 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b8$$udzne
000137962 7001_ $$0P:(DE-HGF)0$$aWalch, Axel$$b9
000137962 7001_ $$0P:(DE-HGF)0$$aUrsini, Fulvio$$b10
000137962 7001_ $$0P:(DE-HGF)0$$aFriedmann Angeli, José Pedro$$b11
000137962 7001_ $$0P:(DE-HGF)0$$aConrad, Marcus$$b12$$eCorresponding author
000137962 77318 $$2Crossref$$3journal-article$$a10.1074/jbc.m115.656363$$b : American Society for Biochemistry & Molecular Biology (ASBMB), 2015-04-28$$n23$$p14668-14678$$tJournal of Biological Chemistry$$v290$$x0021-9258$$y2015
000137962 773__ $$0PERI:(DE-600)1474604-9$$a10.1074/jbc.M115.656363$$gVol. 290, no. 23, p. 14668 - 14678$$n23$$p14668-14678$$q290:23<14668 - 14678$$tThe journal of biological chemistry$$v290$$x0021-9258$$y2015
000137962 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505533
000137962 909CO $$ooai:pub.dzne.de:137962$$pVDB
000137962 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2000028$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b8$$kDZNE
000137962 9131_ $$0G:(DE-HGF)POF3-342$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$aDE-HGF$$bForschungsbereich Gesundheit$$lErkrankungen des Nervensystems$$vDisease Mechanisms and Model Systems$$x0
000137962 9141_ $$y2015
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