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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 \u03b14\u03b23 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.<\/jats:p>","DOI":"10.3390\/ijms231710069","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T05:17:23Z","timestamp":1662441443000},"page":"10069","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Membrane-Bound EMC10 Is Required for Sperm Motility via Maintaining the Homeostasis of Cytoplasm Sodium in Sperm"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2717-0224","authenticated-orcid":false,"given":"Lijie","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanhua","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuangyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2804-4019","authenticated-orcid":false,"given":"Jiarong","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuoshuo","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Guo","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Yang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongwen","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuquan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Diao","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Embryo Original Diseases, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2980-4363","authenticated-orcid":false,"given":"Xuanchun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.eururo.2021.08.014","article-title":"European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2021 Update on Male Infertility","volume":"80","author":"Minhas","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.clinbiochem.2018.03.012","article-title":"Fertility and infertility: Definition and epidemiology","volume":"62","author":"Wyns","year":"2018","journal-title":"Clin. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/1471-0528.14966","article-title":"Epidemiology of infertility in China: A population-based study","volume":"125","author":"Zhou","year":"2018","journal-title":"BJOG"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S0889-8529(03)00047-1","article-title":"Male factor infertility","volume":"32","author":"Brugh","year":"2003","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41585-018-0003-3","article-title":"Genetics of male infertility","volume":"15","author":"Krausz","year":"2018","journal-title":"Nat. Rev. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1093\/jmcb\/mjy024","article-title":"EMC10 governs male fertility via maintaining sperm ion balance","volume":"10","author":"Zhou","year":"2018","journal-title":"J. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/s41586-020-2389-3","article-title":"Structure of the ER membrane complex, a transmembrane-domain insertase","volume":"584","author":"Bai","year":"2020","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s11060-010-0314-6","article-title":"hHSS1: A novel secreted factor and suppressor of glioma growth located at chromosome 19q13.33","volume":"102","author":"Gallaher","year":"2011","journal-title":"J. Neuro Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1677\/JOE-09-0086","article-title":"Molecular cloning of a novel secreted peptide, INM02, and regulation of its expression by glucose","volume":"202","author":"Wang","year":"2009","journal-title":"J. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1161\/CIRCULATIONAHA.117.029980","article-title":"EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subunit 10) Is a Bone Marrow-Derived Angiogenic Growth Factor Promoting Tissue Repair After Myocardial Infarction","volume":"136","author":"Reboll","year":"2017","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e62611","DOI":"10.7554\/eLife.62611","article-title":"Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients","volume":"9","author":"Brauning","year":"2020","journal-title":"eLife"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1677\/erc.0.0110295","article-title":"Gene expression profiling in human insulinoma tissue: Genes involved in the insulin secretion pathway and cloning of novel full-length cDNAs","volume":"11","author":"Wang","year":"2004","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Junes-Gill, K.S., Lawrence, C.E., Wheeler, C.J., Cordner, R., Gill, T.G., Mar, V., Shiri, L., and Basile, L.A. (2014). Human Hematopoietic Signal peptide-containing Secreted 1 (hHSS1) modulates genes and pathways in glioma: Implications for the regulation of tumorigenicity and angiogenesis. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-920"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.cell.2012.11.052","article-title":"Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion","volume":"152","author":"Xu","year":"2013","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"E6127","DOI":"10.1073\/pnas.1615719114","article-title":"Loss-of-function mutation in Mirta22\/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion","volume":"114","author":"Diamantopoulou","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/cge.13842","article-title":"EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay","volume":"98","author":"Umair","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1038\/s41436-021-01097-x","article-title":"A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features","volume":"23","author":"Shao","year":"2021","journal-title":"Genet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ejpn.2022.01.012","article-title":"The phenotype of homozygous EMC10 variant: A new syndrome with intellectual disability and language impairment","volume":"37","author":"Gur","year":"2022","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"R229","DOI":"10.1016\/j.cub.2019.01.003","article-title":"Protein glycosylation","volume":"29","author":"Eichler","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/0014-4827(92)90291-F","article-title":"Immortalization of germ cells and somatic testicular cells using the SV40 large T antigen","volume":"201","author":"Hofmann","year":"1992","journal-title":"Exp. Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5533","DOI":"10.1073\/pnas.91.12.5533","article-title":"Immortalized germ cells undergo meiosis in vitro","volume":"91","author":"Hofmann","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nowicka-Bauer, K., and Szymczak-Cendlak, M. (2021). Structure and Function of Ion Channels Regulating Sperm Motility\u2014An Overview. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063259"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1146\/annurev.biochem.71.102201.141218","article-title":"Biochemistry of Na,K-ATPase","volume":"71","author":"Kaplan","year":"2002","journal-title":"Annu. Rev. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13661","DOI":"10.1021\/bi991207b","article-title":"Functional characterization of a testes-specific alpha-subunit isoform of the sodium\/potassium adenosinetriphosphatase","volume":"38","author":"Blanco","year":"1999","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1530\/rep.1.00806","article-title":"Different expression and activity of the alpha1 and alpha4 isoforms of the Na,K-ATPase during rat male germ cell ontogeny","volume":"130","author":"Wagoner","year":"2005","journal-title":"Reproduction"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1530\/rep.1.00612","article-title":"Sperm channel diversity and functional multiplicity","volume":"131","author":"Darszon","year":"2006","journal-title":"Reproduction"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1073\/pnas.1016902108","article-title":"Na,K-ATPase alpha4 isoform is essential for sperm fertility","volume":"108","author":"Jimenez","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1093\/biolre\/ioaa093","article-title":"The Na+ and K+ transport system of sperm (ATP1A4) is essential for male fertility and an attractive target for male contraceptiondagger","volume":"103","author":"Syeda","year":"2020","journal-title":"Biol. Reprod."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1007\/s10815-021-02087-3","article-title":"Na,K-ATPase Atp1a4 isoform is important for maintaining sperm flagellar shape","volume":"38","author":"McDermott","year":"2021","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1095\/biolreprod.110.087064","article-title":"Increased expression of the Na,K-ATPase alpha4 isoform enhances sperm motility in transgenic mice","volume":"84","author":"Jimenez","year":"2011","journal-title":"Biol. Reprod."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.fertnstert.2021.12.012","article-title":"The sixth edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen: Ensuring quality and standardization in basic examination of human ejaculates","volume":"117","author":"Bjorndahl","year":"2022","journal-title":"Fertil. Steril."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1056\/NEJMoa003005","article-title":"Sperm morphology, motility, and concentration in fertile and infertile men","volume":"345","author":"Guzick","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/978-3-030-21664-1_6","article-title":"Sperm DNA Fragmentation: Consequences for Reproduction","volume":"1166","author":"Simon","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00018-019-03253-8","article-title":"Oxidative stress and male infertility: Current knowledge of pathophysiology and role of antioxidant therapy in disease management","volume":"77","author":"Barati","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.juro.2008.10.158","article-title":"Seminal plasma survivin in fertile and infertile males","volume":"181","author":"Roshdy","year":"2009","journal-title":"J. Urol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1530\/REP-15-0138","article-title":"Cholecystokinin receptors regulate sperm protein tyrosine phosphorylation via uptake of HCO3","volume":"150","author":"Zhou","year":"2015","journal-title":"Reproduction"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1530\/jrf.0.0810127","article-title":"Specific labelling by peanut agglutinin of the outer acrosomal membrane of the human spermatozoon","volume":"81","author":"Mortimer","year":"1987","journal-title":"J. Reprod. Fertil."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/10069\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:22:49Z","timestamp":1760142169000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/10069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,3]]},"references-count":37,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231710069"],"URL":"https:\/\/doi.org\/10.3390\/ijms231710069","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,3]]}}}