Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice
Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice
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DOI：
10.1074/jbc.m109.016139
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发表时间：
2009-11-20
影响因子：
4.8
通讯作者：
Nakagawa, Yasuhito
中科院分区：
文献类型：
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作者：
Imai, Hirotaka;Hakkaku, Nao;Nakagawa, Yasuhito
磷脂氢过氧化物谷胱甘肽过氧化物酶（GPx 4）是一种细胞内的抗氧化酶，可直接还原过氧化磷脂。GPx 4在睾丸和精子的线粒体中强烈表达。我们先前发现来自30%诊断为少弱精子症的不育人类男性的精子中GPx 4的表达显著降低（Imai，H.，铃木，K.，Ishizaka，K.，Ichinose，S.，大岛，H.，冈安岛Emoto，K.，梅田，M.，Nakagawa，Y.等人（2001）Biol. Reprod. 64，674-683）。为了阐明精母细胞中GPx 4缺陷是否导致男性不育，我们使用CreloxP系统建立了精母细胞特异性GPx 4敲除小鼠。所有的精细胞特异性GPx 4基因敲除雄性小鼠被发现是不育的，尽管正常的栓形成交配后，精子数量显着减少。附睾GPx 4基因缺失的精子不能使卵母细胞体外受精。这些精子的前向运动和线粒体膜电位显着降低。这些损害伴随着结构异常，如在中段的发夹状鞭毛弯曲和线粒体肿胀的精子。这些结果表明，精母细胞中GPx 4的缺失导致精子严重异常。这可能是小鼠和人类雄性不育的原因之一。
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.