Spermatogenic cell-specific type 1 hexokinase (HK1S) is essential for capacitation-associated increase in tyrosine phosphorylation and male fertility in mice.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Hexokinase*/genetics ; Hexokinase*/metabolism ; Spermatozoa*/metabolism ; Mice, Knockout* ; Sperm Capacitation*/genetics ; Infertility, Male*/genetics ; Infertility, Male*/metabolism ; Fertility*/genetics ; Tyrosine*/metabolism; Animals ; Male ; Mice ; Phosphorylation ; Female ; Testis/metabolism ; Sperm Motility/genetics ; Glycolysis ; Spermatogenesis/genetics

Hexokinase (HK) catalyzes the first irreversible rate-limiting step in glycolysis that converts glucose to glucose-6-phosphate. HK1 is ubiquitously expressed in the brain, erythrocytes, and other tissues where glycolysis serves as the major source of ATP production. Spermatogenic cell-specific type 1 hexokinase (HK1S) is expressed in sperm but its physiological role in male mice is still unknown. In this study, we generate Hk1s knockout mice using the CRISPR/Cas9 system to study the gene function in vivo. Hk1s mRNA is exclusively expressed in testes starting from postnatal day 18 and continuing to adulthood. HK1S protein is specifically localized in the outer surface of the sperm fibrous sheath (FS). Depletion of Hk1s leads to infertility in male mice and reduces sperm glycolytic pathway activity, yet they have normal motile parameters and ATP levels. In addition, by using in vitro fertilization (IVF), Hk1s deficient sperms are unable to fertilize cumulus-intact or cumulus-free oocytes, but can normally fertilize zona pellucida-free oocytes. Moreover, Hk1s deficiency impairs sperm migration into the oviduct, reduces acrosome reaction, and prevents capacitation-associated increases in tyrosine phosphorylation, which are probable causes of infertility. Taken together, our results reveal that HK1S plays a critical role in sperm function and male fertility in mice.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Tian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

J Vis Exp. 2019 Sep 17;(151):. (PMID: 31609338)
J Cell Physiol. 2008 Dec;217(3):745-51. (PMID: 18683212)
Development. 2013 Nov;140(22):4471-9. (PMID: 24194470)
Mol Cell Biol. 1987 Sep;7(9):3107-12. (PMID: 2823118)
Biol Reprod. 2010 Mar;82(3):504-15. (PMID: 19889946)
J Reprod Infertil. 2009 Oct;10(3):185-91. (PMID: 23926467)
Biol Reprod. 2013 Apr 11;88(4):90. (PMID: 23446454)
Mol Cell Proteomics. 2006 May;5(5):801-10. (PMID: 16452089)
Biochem Med Metab Biol. 1991 Jun;45(3):271-91. (PMID: 1710914)
G3 (Bethesda). 2019 Feb 7;9(2):591-599. (PMID: 30591434)
Reproduction. 2015 Mar;149(3):235-44. (PMID: 25504869)
Biol Reprod. 2008 Jul;79(1):26-34. (PMID: 18367675)
Biol Reprod. 2017 Oct 1;97(4):586-597. (PMID: 29025010)
Sci Adv. 2023 Jan 25;9(4):eade7607. (PMID: 36696506)
Biol Reprod. 2001 May;64(5):1350-7. (PMID: 11319138)
Dev Biol. 2007 Sep 1;309(1):18-31. (PMID: 17659271)
Mol Reprod Dev. 2008 Apr;75(4):632-40. (PMID: 17924400)
Tohoku J Exp Med. 1991 Oct;165(2):99-104. (PMID: 1812597)
Microsc Res Tech. 2003 May 1;61(1):103-15. (PMID: 12672126)
Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16501-6. (PMID: 15546993)
Mol Cell. 2022 Apr 7;82(7):1261-1277.e9. (PMID: 35305311)
J Biol Chem. 1994 Feb 4;269(5):3810-7. (PMID: 7508920)
J Biol Chem. 2001 Mar 9;276(10):7630-6. (PMID: 11115497)
Cell Metab. 2017 Jul 5;26(1):131-141. (PMID: 28683280)
Biol Reprod. 2004 Aug;71(2):540-7. (PMID: 15084484)
Redox Biol. 2021 Nov 1;48:102176. (PMID: 34753004)
J Cell Physiol. 2020 Sep;235(9):6058-6072. (PMID: 32020604)
Biomed Res Int. 2014;2014:902953. (PMID: 24791005)
Biol Reprod. 1998 Mar;58(3):834-41. (PMID: 9510974)
Mol Reprod Dev. 1996 May;44(1):14-22. (PMID: 8722688)
Biol Reprod. 1992 May;46(5):869-78. (PMID: 1375514)
Biol Reprod. 2006 Aug;75(2):270-8. (PMID: 16687649)
J Androl. 2001 Jul-Aug;22(4):680-95. (PMID: 11451366)
Br J Haematol. 2019 Sep;186(5):e142-e145. (PMID: 31119733)
Proc Natl Acad Sci U S A. 1987 Aug;84(15):5311-5. (PMID: 2440048)
Mol Cell Proteomics. 2013 Feb;12(2):330-42. (PMID: 23161514)
Mol Reprod Dev. 1996 Jan;43(1):82-93. (PMID: 8720117)
FASEB J. 2020 Apr;34(4):5389-5400. (PMID: 32072696)
J Reprod Fertil. 1981 Jan;61(1):25-35. (PMID: 7452624)
Mol Cell Biol. 2002 Aug;22(15):5554-62. (PMID: 12101247)
Adv Anat Embryol Cell Biol. 2016;220:93-106. (PMID: 27194351)
Nature. 1958 Mar 22;181(4612):851. (PMID: 13526698)
Biol Reprod. 2010 Jan;82(1):136-45. (PMID: 19759366)
Mol Reprod Dev. 1998 Apr;49(4):374-85. (PMID: 9508088)
J Exp Biol. 2003 Jun;206(Pt 12):2049-57. (PMID: 12756287)
J Biol Chem. 2010 Mar 12;285(11):7977-85. (PMID: 20068039)
Biol Reprod. 1993 Aug;49(2):191-203. (PMID: 8396993)
Biol Reprod. 2022 Aug 9;107(2):619-634. (PMID: 35403672)
J Biol Chem. 2018 Jun 15;293(24):9435-9447. (PMID: 29700114)
Cell Rep. 2021 Apr 20;35(3):109025. (PMID: 33882315)

EC 2.7.1.1 (Hexokinase)
42HK56048U (Tyrosine)
EC 2.7.1.1 (HK1 protein, mouse)

Date Created: 20240729 Date Completed: 20240729 Latest Revision: 20240731

20240731

PMC11285943

10.1371/journal.pgen.1011357

39074078