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EMC10 governs male fertility via maintaining sperm ion balance Free
Yuchuan Zhou 1 , Fei Wu 2 , Man Zhang 3 , Zuquan Xiong 2 , Qianqian Yin 1 , Yanfei Ru 1 , Huijuan Shi 4 ,Jinsong Li 3 , Shanhua Mao 2 , Yanliang Li 5 , Xinyi Cao 5 , Renming Hu 5 , Chong Wee Liew 6 ,Qiang Ding 2,* , Xuanchun Wang 5,* , and Yonglian Zhang 1,*
1 State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
2 Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
3 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
4 China National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Shanghai Institute of Planned Parenthood Research,Shanghai 200030, China
5 Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China
6 Department of Physiology & Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
*Correspondence to:* Correspondence to: Qiang Ding, E-mail: dr_dingqiang@hotmail.com; Xuanchun Wang, E-mail: wangxch@fudan.edu.cn; Yonglian Zhang, E-mail: ylzhang@ sibcb.ac.cn
J Mol Cell Biol, Volume 10, Issue 6, December 2018, Pages 503-514  https://doi.org/10.1093/jmcb/mjy024
Keyword: Emc10 knockout, sperm maturation, male infertility, ion imbalance, Na/K-ATPase

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.