Extra-mitochondrial citrate synthase initiates calcium oscillation and suppresses age-dependent sperm dysfunction.,Laboratory Investigation

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Extra-mitochondrial citrate synthase initiates calcium oscillation and suppresses age-dependent sperm dysfunction.
Laboratory Investigation ( IF 5.1 ) Pub Date : 2019-12-19 , DOI: 10.1038/s41374-019-0353-3
Woojin Kang _{1,

2} , Yuichirou Harada _{1,

3} , Kenji Yamatoya ₄ , Natsuko Kawano _{1,

5} , Seiya Kanai ₅ , Yoshitaka Miyamoto ₁ , Akihiro Nakamura ₁ , Mami Miyado ₆ , Yoshiki Hayashi ₇ , Yoko Kuroki ₈ , Hidekazu Saito ₂ , Yasuhiro Iwao ₉ , Akihiro Umezawa ₁ , Kenji Miyado ₁

Affiliation

Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
Department of Perinatal Medicine and Maternal Care, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku, Tokyo, 160-8402, Japan.
Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Urayasu-City, Chiba, 279-0021, Japan.
Department of Life Sciences, School of Agriculture, Meiji University, 1-1-1 Higashi-Mita, Tama-ku, Kawasaki-shi, Kanagawa, 214-8571, Japan.
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
Department of Genome Medicine, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
Division of Earth Science, Biology, and Chemistry, Graduate School of Sciences and Technology for Innovation, Yamaguchi University, 1677-1 Yoshida, Yamaguchi City, Yamaguchi, 753-8511, Japan.

Men and women become infertile with age, but the mechanism of declining male fertility, more specifically, the decrease in in sperm quality, is not well known. Citrate synthase (CS) is a core enzyme of the mitochondrial tricarboxylic acid (TCA) cycle, which directly controls cellular function. Extra-mitochondrial CS (eCS) is produced and abundant in the sperm head; however, its role in male fertility is unknown. We investigated the role of eCS in male fertility by producing eCs-deficient (eCs-KO) mice. The initiation of the first spike of Ca2+ oscillation was substantially delayed in egg fused with eCs-KO sperm, despite normal expression of sperm factor phospholipase C zeta 1. The eCs-KO male mice were initially fertile, but the fertility dropped with age. Metabolomic analysis of aged sperm revealed that the loss of eCS enhances TCA cycle in the mitochondria with age, presumably leading to depletion of extra-mitochondrial citrate. The data suggest that eCS suppresses age-dependent male infertility, providing insights into the decline of male fertility with age.

中文翻译：

线粒体外柠檬酸合酶启动钙振荡并抑制年龄依赖性精子功能障碍。

男性和女性随着年龄的增长而变得不育，但男性生育能力下降的机制，更具体地说，精子质量下降，尚不清楚。柠檬酸合酶 (CS) 是线粒体三羧酸 (TCA) 循环的核心酶，它直接控制细胞功能。线粒体外 CS (eCS) 在精子头部产生并大量存在；然而，它在男性生育能力中的作用尚不清楚。我们通过生产缺乏 eCs (eCs-KO) 的小鼠来研究 eCS 在雄性生育能力中的作用。尽管精子因子磷脂酶 C zeta 1 的表达正常，但在与 eCs-KO 精子融合的卵子中，Ca2+ 振荡的第一个尖峰的启动显着延迟。eCs-KO 雄性小鼠最初是可育的，但随着年龄的增长，生育能力下降。老化精子的代谢组学分析显示，随着年龄的增长，eCS 的丢失增强了线粒体中的 TCA 循环，可能导致线粒体外柠檬酸盐的耗尽。数据表明，eCS 抑制了年龄依赖性男性不育症，提供了对男性生育能力随年龄下降的见解。

更新日期：2019-12-20

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