Groundbreaking discovery uncovers a vital switch in sperm motility
Infertility affects about one in six couples, and male factors contribute to roughly half of these cases. A new study from the University of Osaka identifies a crucial protein complex that keeps sperm moving, offering a promising path for improved diagnosis and treatment of male infertility. The team demonstrates that a specific molecular switch controls the signaling that powers sperm tail motion, and that restoring this switch can rescue sperm motility and fertility in mice.
How sperm movement is powered
For fertilization, sperm must swim effectively to reach the egg. This movement is driven by the tail, or flagellum, and is regulated by cyclic AMP (cAMP), a key signaling molecule. While scientists had long known that the enzyme soluble adenylyl cyclase (sAC) produces cAMP inside sperm, the mechanisms ensuring sAC’s stability and activity were not fully understood.
The TMEM217–SLC9C1 partnership
The Osaka researchers focused on TMEM217, a protein produced specifically in the testes with an unclear function. They engineered mice that could not produce TMEM217 and found that these males were completely infertile; their sperm were almost entirely immotile. Further investigation revealed that TMEM217 partners with another protein, SLC9C1, to form a stable complex. This TMEM217–SLC9C1 complex is essential for maintaining sAC levels in mature sperm.
Consequences of losing the switch
Without TMEM217, SLC9C1 becomes unstable and is lost, leading to a sharp decline in sAC. As a result, cAMP levels plummet, and sperm lose their motility. In effect, the TMEM217–SLC9C1–sAC axis acts as a “switch” that keeps the movement signal alive during sperm maturation and transport.
Restoring movement and fertility in the lab
In a pivotal experiment, the researchers treated immotile sperm from TMEM217-deficient mice with a cAMP analog, a molecule that mimics cAMP’s action. This intervention successfully reactivated movement and enabled fertilization of eggs in vitro, culminating in the birth of healthy puppies in the study. The result demonstrates that the motility defect is reversible when the cAMP signaling pathway is reactivated, bypassing the need for the missing TMEM217–SLC9C1 complex.
Implications for human infertility
The TMEM217–SLC9C1–sAC axis provides a new target for diagnosing unexplained male infertility and for developing potential therapies. By focusing on the stability of sAC and the integrity of the TMEM217–SLC9C1 complex, clinicians may be able to identify men whose sperm motility problems stem from disruptions in this signaling switch. Moreover, strategies that mimic or boost cAMP signaling could offer a new class of treatments for certain forms of male infertility.
Expert perspective
Professor Masahito Ikawa, senior author of the study, commented, “We pinpointed a simple way to restart immotile sperm by adding a cAMP analog. It’s an encouraging step toward practical options for some forms of male infertility.”
Looking ahead
While the findings illuminate a central mechanism behind sperm motility, translating this knowledge into human therapies will require careful clinical investigation. The study lays a solid foundation for exploring diagnostic tests that assess the TMEM217–SLC9C1–sAC axis in men facing infertility and for developing targeted treatments that restore proper cAMP signaling in sperm.
