Sperm Phosphoproteome: Unraveling Male Infertility

Simple Summary Approximately 24% of men referred to assisted reproductive technology (ART) present with idiopathic male infertility. The current standard analysis of human semen does not allow for an accurate diagnosis of this infertility with unknown etiology. Spermatozoa cellular development and maturation, as well the acquisition of suitable motility and capacitation, are tightly coordinated by sperm protein phosphorylation, among other protein post-translational modifications. Extraordinary advances have been achieved in the field of spermatozoa using proteomics methodology in combination with bioinformatics. The aim of this work is to review, using a proteomic and phosphoproteomic analysis, the updated knowledge about proteins and phosphoproteins of spermatozoa that regulate cell processes necessary to achieve a proper fertilization. The phosphorylation of sperm proteins involved in spermatogenesis, in sperm capacitation, and in the maintenance of correct sperm motility, and consequently in sperm quality, is focused on in this review. Further investigations of protein spermatozoa in larger populations combined with other multi-omics technologies would offer a precise perspective of male fertility and would be especially relevant for those cases involving repeated failures in ART linked to idiopathic infertility. Infertility affects approximately 15% of couples worldwide of childbearing age, and in many cases the etiology of male infertility is unknown. The current standard evaluation of semen is insufficient to establish an accurate diagnosis. Proteomics techniques, such as phosphoproteomics, applied in this field are a powerful tool to understand the mechanisms that regulate sperm functions such as motility, which is essential for successful fertilization. Among the post-translational modifications of sperm proteins, this review summarizes, from a proteomic perspective, the updated knowledge of protein phosphorylation, in human spermatozoa, as a relevant molecular mechanism involved in the regulation of sperm physiology. Specifically, the role of sperm protein phosphorylation in motility and, consequently, in sperm quality is highlighted. Additionally, through the analysis of published comparative phosphoproteomic studies, some candidate human sperm phosphoproteins associated with low sperm motility are proposed. Despite the remarkable advances in phosphoproteomics technologies, the relatively low number of studies performed in human spermatozoa suggests that phosphoproteomics has not been applied to its full potential in studying male infertility yet. Therefore, further studies will improve the application of this procedure and overcome the limitations, increasing the understanding of regulatory mechanisms underlying protein phosphorylation in sperm motility and, consequently, in male fertility.

Automated summary

Approximately 24% of men undergoing assisted reproductive technology (ART) have idiopathic male infertility, which cannot be accurately diagnosed by current standard semen analysis. Proteomics, especially phosphoproteomics, has provided valuable insights into the regulation of sperm functions, such as motility, and male fertility. Further studies combining proteomic techniques with other omics technologies could enhance our understanding of the molecular mechanisms underlying sperm physiology and quality.