Extra-mitochondrial citrate synthase initiates calcium oscillation and suppresses age-dependent sperm dysfunction
Extra-mitochondrial citrate synthase initiates calcium oscillation and suppresses age-dependent sperm dysfunction
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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
DOI：
10.1038/s41374-019-0353-3
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发表时间：
2020-04-01
影响因子：
5
通讯作者：
Miyado, Kenji
中科院分区：
文献类型：
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作者：
Kang, Woojin;Harada, Yuichirou;Miyado, Kenji
随着年龄的增长，男性和女性都变得不育，但男性生育能力下降的机制，更具体地说，是精子质量的下降，尚不清楚。柠檬酸合成酶（Citrate synthase， CS）是线粒体三羧酸（TCA）循环的核心酶，直接控制细胞功能。线粒体外CS （Extra-mitochondrial CS, eCS）在精子头部大量产生；然而，它在男性生育能力中的作用尚不清楚。我们通过制造eCS缺陷（eCS - ko）小鼠来研究eCS在雄性生育能力中的作用。在与ec - ko精子融合的卵子中，尽管精子因子磷脂酶czeta 1表达正常，但Ca2+振荡的第一个峰的起始时间大大延迟。eCs-KO雄性小鼠最初具有生育能力，但随着年龄的增长，生育能力下降。衰老精子的代谢组学分析显示，随着年龄的增长，eCS的缺失会增强线粒体中的TCA循环，这可能导致线粒体外柠檬酸盐的消耗。数据表明，eCS抑制年龄依赖性男性不育症，为男性生育能力随年龄下降提供了见解。柠檬酸合酶是三羧酸循环的核心酶，但线粒体外CS （eCS）的作用尚不清楚。在精子头部丰富的eCS，以不依赖于磷脂酶czeta 1的方式触发卵子Ca2+振荡的第一个峰值。此外，敲除eCS的雄性小鼠的生育能力随着年龄的增长而下降，这表明eCS通过加速Ca2+振荡来抑制年龄依赖性精子功能障碍。
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.Citrate synthase is a core enzyme of tricarboxylic acid cycle, but the role of extra-mitochondrial CS (eCS) is less clear. eCS, abundant in the sperm head, triggers a first spike of egg Ca2+ oscillation in a phospholipase C zeta 1 -independent manner. Moreover, the fertility of eCs-knockout male mice dropped with age, indicating that eCS suppresses age-dependent sperm dysfunction by accelerating Ca2+ oscillation.