Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice.
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.
School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. imaih@pharm.kitasato-u.ac.jp
Hirotaka
H
Imai
Nao
N
Hakkaku
Ryo
R
Iwamoto
Jyunko
J
Suzuki
Toshiyuki
T
Suzuki
Yoko
Y
Tajima
Kumiko
K
Konishi
Shintaro
S
Minami
Shizuko
S
Ichinose
Kazuhiro
K
Ishizaka
Seiji
S
Shioda
Satoru
S
Arata
Masuhiro
M
Nishimura
Shinsaku
S
Naito
Yasuhito
Y
Nakagawa
D000818:Animals; D004822:Epididymis / Q000378:metabolism; D005260:Female; D005307:Fertilization in Vitro; D005979:Glutathione Peroxidase / Q000378:metabolism*; D007248:Infertility, Male / Q000201:enzymology*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D017382:Reactive Oxygen Species; D013090:Spermatocytes / Q000201:enzymology*; D013997:Time Factors
D017382:Reactive Oxygen Species; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase