Study uncovers key protein complex controlling sperm motility and male fertility

Infertility affects about one in six couples, and male factors account for roughly half of all cases-often because sperm don't swim well. Researchers from the University of Osaka uncovered a key component of the "switch" that keeps the movement signal strong, offering a promising new avenue for both diagnosis and treatment. When this switch is absent, sperm slow down, and fertilization fails. By restoring that signal in the lab, the team rescued swimming and achieved healthy births in mice.

For sperm to successfully fertilize an egg, they must be able to swim, a process driven by their tail. This movement is activated by an essential signaling molecule called cyclic AMP (cAMP). While it was known that an enzyme named soluble adenylyl cyclase (sAC) produces cAMP inside sperm, the precise mechanism controlling this enzyme's stability and function remained largely a mystery.

The research team focused on a protein with a previously unknown function, TMEM217, which is produced specifically in the testes. They engineered mice that could not produce TMEM217 and found that the males were completely infertile, with sperm that were almost entirely immotile. Further investigation revealed that TMEM217 partners with another protein, SLC9C1, to form a stable complex.

This complex is crucial for maintaining the presence of the sAC in mature sperm. Without TMEM217, SLC9C1 is lost and sAC is markedly reduced, causing cAMP levels to plummet and sperm motility to fail. In a significant breakthrough, the team took the immotile sperm from these mice and treated them with a cAMP analog-a molecule that mimics cAMP. This treatment successfully restored the sperm's movement and enabled them to fertilize eggs in vitro, leading to the birth of healthy pups.

This study has revealed a fundamental "switch" in sperm, providing a deeper understanding of sperm motility regulation. The discovery of the TMEM217-SLC9C1-sAC axis offers a new target for diagnosing unexplained cases of male infertility.

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."

Professor Masahito Ikawa, senior author of the study