Mitochondrial glutathione peroxidase 4 disruption causes male infertility

Schneider, Manuela; Förster, Heidi; Boersma, Auke; Seiler, Alexander; Wehnes, Helga; Sinowatz, Fred; Neumüller, Christine; Deutsch, Manuel J.; Walch, Axel; Angelis, Martin Hrabé de; Wurst, Wolfgang; Ursini, Fulvio; Roveri, Antonella; Maleszewski, Marek; Maiorino, Matilde; Conrad, Marcus

doi:10.1096/fj.09-132795

Cited by 267 publications

(214 citation statements)

References 36 publications

(46 reference statements)

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“…These results suggest that mitochondrial dysfunction in spermatozoa is a major functional defect brought on by GPx4 deficiency. During submission of the manuscript for this report, Conrad and his colleagues demonstrated that depletion of mitochondrial GPx4 causes impaired sperm quality, severe structural abnormalities, and male infertility (35), which also confirms our ideas.…”

Section: Discussionsupporting

confidence: 84%

Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice

Imai

Hakkaku

Iwamoto

et al. 2009

Journal of Biological Chemistry

176

141

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Phospholipid hydroperoxide glutathione peroxidase (GPx4) is an intracellular antioxidant enzyme that directly reduces peroxidized phospholipids. GPx4 is strongly expressed in the mitochondria of testis and spermatozoa. We previously found a significant decrease in the expression of GPx4 in spermatozoa from 30% of infertile human males diagnosed with oligoasthenozoospermia (Imai, H., Suzuki, K., Ishizaka, K., Ichinose, S., Oshima, H., Okayasu, I., Emoto, K., Umeda, M., and Nakagawa, Y. (2001) Biol. Reprod. 64, 674 -683). To clarify whether defective GPx4 in spermatocytes causes male infertility, we established spermatocyte-specific GPx4 knock-out mice using a CreloxP system. All the spermatocyte-specific GPx4 knock-out male mice were found to be infertile despite normal plug formation after mating and displayed a significant decrease in the number of spermatozoa. Isolated epididymal GPx4-null spermatozoa could not fertilize oocytes in vitro. These spermatozoa showed significant reductions of forward motility and the mitochondrial membrane potential. These impairments were accompanied by the structural abnormality, such as a hairpin-like flagella bend at the midpiece and swelling of mitochondria in the spermatozoa. These results demonstrate that the depletion of GPx4 in spermatocytes causes severe abnormalities in spermatozoa. This may be one of the causes of male infertility in mice and humans.A frequent cause of male infertility is defective sperm function, which is the main problem for close to a quarter of couples who attend infertility clinics (1-4). Considerable efforts are now focused on the identifying ultrastructural and/or molecular defects in the spermatozoa or seminal plasma to develop solutions to various types of male infertility.Phospholipid hydroperoxide glutathione peroxidase (GPx4) 2 is an intracellular selenoprotein that directly reduces peroxidized phospholipids produced in cell membranes (5). The GPx4 gene has a complex intron/exon structure (6, 7). Three different transcripts of GPx4 exist, differing in their 5Ј extension and coding for a cytosolic protein (non-mitochondrial GPx4), a mitochondrial protein (mitochondrial GPx4), and a nuclear protein (nucleolar GPx4), respectively (6, 7). After cleavage of the N-terminal mitochondrial import sequence of mitochondrial GPx4, the mature protein becomes identical to the 20-kDa non-mitochondrial GPx4 (8, 9). Nuclear GPx4 was recently identified as a sperm nucleus-specific 34-kDa selenoprotein (called snGPx, for sperm nucleus-specific glutathione peroxidase) (10). It is formed by use of an alternative promoter and start codon localized in the first intron of the GPx4 gene (7, 10, 11). We previously reported that 34-kDa GPx4 localized in nucleoli in several cell lines by using an N-terminal nucleolar import signal (11). We call hereafter nuclear GPx4 nucleolar GPx4, because non-mitochondrial 20-kDa GPx4 exists both in cytosol and in the nucleus (12). Expression of three types of GPx4 is induced significantly in testis during spermatogenesis, especiall...

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Section: Discussionsupporting

confidence: 84%

Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice

Imai

Hakkaku

Iwamoto

et al. 2009

Journal of Biological Chemistry

176

141

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“…IVF experiments were performed as described previously (25). Sperm quality was measured using an IVOS Sperm Analyzer (version 12.1c; Hamilton Research) as previously described (26). The motility (percentage of all motile spermatozoa) and progressivity (percentage of spermatozoa with a minimum velocity of Ն60 m/second and straightness of Ն50%) were evaluated.…”

Section: Methodsmentioning

confidence: 99%

A novel N‐ethyl‐N‐nitrosourea–induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model

Abe¹,

Fuchs²,

Boersma³

et al. 2011

Arthritis & Rheumatism

Self Cite

138

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Objective. It is difficult to identify a single causative factor for inflammatory arthritis because of the multifactorial nature of the disease. This study was undertaken to dissect the molecular complexity of systemic inflammatory disease, utilizing a combined approach of mutagenesis and systematic phenotype screening in a murine model.Methods. In a large-scale N-ethyl-N-nitrosourea mutagenesis project, the Ali14 mutant mouse strain was established because of dominant inheritance of spontaneous swelling and inflammation of the hind paws. Genetic mapping and subsequent candidate gene sequencing were conducted to find the causative gene, and systematic phenotyping of Ali14/؉ mice was performed in the German Mouse Clinic. Results.A novel missense mutation in the phospholipase C␥2 gene (Plcg2) was identified in Ali14/؉ mice. Because of the hyperreactive external entry of calcium observed in cultured B cells and other in vitro experiments, the Ali14 mutation is thought to be a novel gain-of-function allele of Plcg2. Findings from systematic screening of Ali14/؉ mice demonstrated various phenotypic changes: an abnormally high T cell:B cell

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“…45 Such programs have revealed many critical genes for human diseases, including male infertility. [46][47][48][49] …”

Section: Mouse Models In Male Fertility Research D Jamsai and Mk O'brmentioning

confidence: 99%

Mouse models in male fertility research

Jamsai¹,

O'Bryan²

2010

Asian J Androl

113

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Limited knowledge of the genetic causes of male infertility has resulted in few treatment and targeted therapeutic options. Although the ideal approach to identify infertility causing mutations is to conduct studies in the human population, this approach has progressed slowly due to the limitations described herein. Given the complexity of male fertility, the entire process cannot be modeled in vitro. As such, animal models, in particular mouse models, provide a valuable alternative for gene identification and experimentation. Since the introduction of molecular biology and recent advances in animal model production, there has been a substantial acceleration in the identification and characterization of genes associated with many diseases, including infertility. Three major types of mouse models are commonly used in biomedical research, including knockout/knockin/gene-trapped, transgenic and chemical-induced point mutant mice. Using these mouse models, over 400 genes essential for male fertility have been revealed. It has, however, been estimated that thousands of genes are involved in the regulation of the complex process of male fertility, as many such genes remain to be characterized. The current review is by no means a comprehensive list of these mouse models, rather it contains examples of how mouse models have advanced our knowledge of post-natal germ cell development and male fertility regulation.

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Mitochondrial glutathione peroxidase 4 disruption causes male infertility

Cited by 267 publications

References 36 publications

Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice

Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice

A novel N‐ethyl‐N‐nitrosourea–induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model

Mouse models in male fertility research

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