Imai Hirotaka, Hakkaku Nao, Iwamoto Ryo, Suzuki Jyunko, Suzuki Toshiyuki, Tajima Yoko, Konishi Kumiko, Minami Shintaro, Ichinose Shizuko, Ishizaka Kazuhiro, Shioda Seiji, Arata Satoru, Nishimura Masuhiro, Naito Shinsaku, Nakagawa Yasuhito
School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
J Biol Chem. 2009 Nov 20;284(47):32522-32. doi: 10.1074/jbc.M109.016139. Epub 2009 Sep 25.
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 Cre-loxP 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.
磷脂氢过氧化物谷胱甘肽过氧化物酶（GPx4）是一种细胞内抗氧化酶，可直接还原过氧化的磷脂。GPx4在睾丸和精子的线粒体中强烈表达。我们之前发现，在诊断为少弱精子症的不育男性中，30%的患者精子中GPx4的表达显著降低（今井浩、铃木健、石坂和、市之濑史、大岛浩、冈安一、江本健、梅田真、中川洋（2001年），《生物繁殖》64卷，674 - 683页）。为了阐明精母细胞中GPx4缺陷是否导致男性不育，我们使用Cre-loxP系统建立了精母细胞特异性GPx4基因敲除小鼠。尽管交配后阴栓形成正常，但所有精母细胞特异性GPx4基因敲除雄性小鼠均不育，且精子数量显著减少。分离的附睾中缺乏GPx4的精子在体外无法使卵母细胞受精。这些精子的向前运动能力和线粒体膜电位显著降低。这些损伤伴随着结构异常，如精子中部出现发夹状鞭毛弯曲以及线粒体肿胀。这些结果表明，精母细胞中GPx4的缺失会导致精子出现严重异常。这可能是小鼠和人类男性不育的原因之一。
