Membrane-Bound EMC10 Is Required for Sperm Motility via Maintaining the Homeostasis of Cytoplasm Sodium in Sperm

Abstract

Endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is an evolutionarily conserved and multifunctional factor across species. We previously reported that Emc10 knockout (KO) leads to mouse male infertility. Emc10-null spermatozoa exhibit multiple aspects of dysfunction, including reduced sperm motility. Two subunits of a Na/K-ATPase, ATP1A4 and ATP1B3, are nearly absent in Emc10 KO spermatozoa. Here, two isoforms of EMC10 were characterized in the mouse testis and epididymis: the membrane-bound (mEMC10) and secreted (scEMC10) isoforms. We present evidence that mEMC10, rather than scEMC10, is required for cytoplasm sodium homeostasis by positively regulating ATP1B3 expression in germ cells. Intra-testis mEMC10 overexpression rescued the sperm motility defect caused by Emc10 KO, while exogenous recombinant scEMC10 protein could not improve the motility of spermatozoa from either Emc10 KO mouse or asthenospermic subjects. Clinically, there is a positive association between ATP1B3 and EMC10 protein levels in human spermatozoa, whereas no correlation was proven between seminal plasma scEMC10 levels and sperm motility. These results highlight the important role of the membrane-bound EMC10 isoform in maintaining cytoplasm sodium homeostasis and sperm motility. Based on the present results, the mEMC10-Na, K/ATPase α4β3 axis is proposed as a novel mechanism underlying the regulation of cytoplasmic sodium and sperm motility, and its components seem to have therapeutic potential for asthenospermia.

ER membrane complex (EMC): Structure, functions, and roles in diseases

“…EMC10‐knockout spermatozoa exhibit nearly absent levels of the two subunits of Na/K‐ATPase, ATP1A4 and ATP1B3. Clinically, there exists a positive correlation between ATP1B3 and EMC10 protein levels in human spermatozoa 89,99 . These observations suggest that EMC10 plays a crucial role in male fertility by participating in the regulation of sperm cytoplasmic sodium ion balance and sperm motility.…”

“…Clinically, there exists a positive correlation between ATP1B3 and EMC10 protein levels in human spermatozoa. 89,99 These observations suggest that EMC10 plays a crucial role in male fertility by participating in the regulation of sperm cytoplasmic sodium ion balance and sperm motility. Furthermore, EMC10 represents a promising biomarker for male fertility and a potential drug target for male infertility treatment.…”