The University of Osaka identifies the protein that controls sperm motility — Function restored by administering artificial reagent to deficient mice

A research group led by Specially Appointed Assistant Professor Rie Iida-Norita, Associate Professor Haruhiko Miyata, and Professor Masahito Ikawa of the Research Institute for Microbial Diseases at the University of Osaka announced that they have discovered that the "TMEM217" protein regulates the production of "cyclic AMP (cAMP)," a molecule that plays a central role in sperm motility. They confirmed that knockout mice become infertile due to immotile sperm, and that sperm motility can be restored by supplementing with molecules that have the same function as cAMP. This discovery is expected to lead to the diagnosis and treatment of male infertility caused by sperm motility dysfunction. The results were published in the Proceedings of the National Academy of Sciences (PNAS) on October 15.

Infertility occurs globally at a high rate of 1 in 6 couples, with half of the causes attributed to the male partner. Approximately 80% of male infertility is caused by decreased sperm motility.

In this study, the research group focused on TMEM217, a protein of previously unknown function that is specifically expressed in the testis.

To clarify the function of this protein, they generated TMEM217-deficient mice and examined their reproductive capacity through mating trials, finding zero offspring and concluding they were infertile.

Microscopic observation showed that sperm from the deficient mice were immotile, revealing that TMEM217 is essential for sperm motility.

Next, to further elucidate its function, they investigated the possibility that it functions by binding to other proteins.

As a result, TMEM217 was found to work together with "SLC9C1," which had been reported to be essential for sperm motility. Furthermore, since SLC9C1 was lost in TMEM217-deficient mice, it was thought that TMEM217 stabilizes SLC9C1, and that both proteins constitute a motility switch.

Sperm can initiate movement when soluble adenylyl cyclase (sAC), an enzyme inside the sperm, produces cAMP, which serves as a signal. If sperm cannot initiate movement, they cannot reach the egg and infertility results; sAC gene mutations have been reported in male infertility patients.

When a cAMP analog (cell-permeable artificial reagent with cAMP function) was added to TMEM217-deficient mouse sperm, sperm motility was restored. When in vitro fertilization was performed by co-culturing this analog with eggs and returning them to the uterus, normal offspring mice were born. No adverse effects on female mice were observed.

Iida-Norita commented: "I am interested in the mechanism, and in terms of applications, I am considering practical research such as whether artificial insemination with sperm supplemented with cAMP analog can succeed. I also want to investigate whether adding cAMP analog shows effects on sperm with low motility due to causes other than TMEM217 deficiency."

Miyata commented: "I have been researching sperm motility for a long time, and restoring motility was a difficult challenge, but I was moved when motility was restored by adding cAMP during this study. In the future, I would like to aim to elucidate the mechanism of how cAMP is produced."

Journal Information
Publication: Proceedings of the National Academy of Sciences (PNAS)
Title: Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility
DOI: 10.1073/pnas.2513924122