EMC10 governs male fertility via maintaining sperm ion balance
EMC10 governs male fertility via maintaining sperm ion balance
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EMC10 通过维持精子离子平衡来控制男性生育能力
DOI：
10.1093/jmcb/mjy024
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发表时间：
2018-12-01
影响因子：
5.5
通讯作者：
Zhang, Yonglian
中科院分区：
文献类型：
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作者：
Zhou, Yuchuan;Wu, Fei;Zhang, Yonglian
不孕不育是一个严重的公共卫生问题，在世界范围内普遍高达15%的育龄夫妇，男性不育占总不育症的一半。转基因动物模型的研究已经发现了许多与男性不育发病相关的基因。然而，根本原因在很大程度上仍不清楚。在这项研究中，我们提供的证据表明，EMC 10，内质网（ER）膜蛋白复合物（EMC）的一个亚基，是男性生育所必需的。EMC 10在弱精子症患者的精子中显著降低，并与人类精子活力呈正相关。缺乏Emc 10基因的雄性小鼠完全不育。Emc 10基因缺失的精子表现出多种缺陷，包括形态异常、运动能力下降、获能受损和顶体反应无力，从而不能获得完整或无ZP的卵母细胞。而卵胞浆内单精子注射可以挽救EMC 10缺失引起的这种缺陷。从机制上讲，EMC 10缺乏导致Na/K-ATP酶失活，进而导致精子细胞内Na+水平升高，从而导致精子活力降低和形态异常。其他机制研究表明，EMC 10的缺乏导致HCO 3进入减少，随后cAMP依赖性蛋白激酶A底物磷酸化和蛋白酪氨酸磷酸化减少。这些数据表明，EMC 10通过维持精子Na+和HCO 3-的离子平衡而对男性生育力不可或缺，并且还表明EMC 10是一种有前途的男性生育力生物标志物和治疗男性不育症的潜在药物靶点。
Infertility is a severe public health problem worldwide that prevails up to 15% in reproductive-age couples, and male infertility accounts for half of total infertility. Studies on genetically modified animal models have identified lots of genes involved in the pathogenesis of male infertility. The underlying causes, however, remain largely unclear. In this study, we provide evidence that EMC10, one subunit of endoplasmic reticulum (ER) membrane protein complex (EMC), is required for male fertility. EMC10 is significantly decreased in spermatozoa from patients with asthenozoospermia and positively associated with human sperm motility. Male mice lacking Emc10 gene are completely sterile. Emc10-null spermatozoa exhibit multiple defects including abnormal morphology, decreased motility, impaired capacitation, and impotency of acrosome reaction, thereby which are incapable of fertilizing intact or ZP-free oocytes. However, intracytoplasmic sperm injection could rescue this defect caused by EMC10 deletion. Mechanistically, EMC10 deficiency leads to inactivation of Na/K-ATPase, in turn giving rise to an increased level of intracellular Na+ in spermatozoa, which contributes to decreased sperm motility and abnormal morphology. Other mechanistic investigations demonstrate that the absence of EMC10 results in a reduction of HCO3- entry and subsequent decreases of both cAMP-dependent protein kinase A substrate phosphorylation and protein tyrosine phosphorylation. These data demonstrate that EMC10 is indispensable to male fertility via maintaining sperm ion balance of Na+ and HCO3-, and also suggest that EMC10 is a promising biomarker for male fertility and a potential pharmaceutical target to treat male infertility.