CatSper-mediated sperm motility is required for mammalian gamete fusion

Abstract Understanding how ion channels control cellular behaviors is a central question in cell biology. CatSper, the main sperm-specific calcium channel, is essential for male fertility in mice and humans through its key role in regulating sperm hyperactivation development and zona pellucida penetration. However, little is known about its involvement in other stages of the fertilization process. Here, we show that CatSper1 knockout sperm not only fail to penetrate the mass of cumulus cells that surrounds the egg, but, unexpectedly, the ability of sperm to fuse with the egg plasma membrane, revealing an unrecognized role of this channel in the gamete membrane fusion step. Notably, sperm energy restriction, a metabolic strategy known to improve sperm function, fully rescued gamete fusion and restored linear sperm motility in mutant sperm revealing, for the first time, that CatSper-mediated sperm motility is required for gamete membrane fusion. These findings identify CatSper as a central player in the entire fertilization process and refine our understanding of the mechanisms underlying mammalian gamete fusion with important implications for both infertility treatment and non-hormonal contraceptive development.