Sperm Phosphoproteome: Unraveling Male Infertility

Abstract

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.

The simultaneous administration of microplastics and cadmium alters rat testicular activity and changes the expression of PTMA, DAAM1 and PREP

“…Currently, especially in the most industrialized states, there is a critical impairment in the quantity and quality of SPZ, implying that the discharge of many pollutants into the environment is a major contributor to reduced fertility ( Selvaraju et al, 2021 ). Furthermore, according to WHO guidelines ( WHO, 2021 ), the seminogram, the analysis of macroscopic (volume, pH, viscosity) and microscopic (concentration, morphology, vitality, and motility of SPZ) characteristics is, to date, the best and most routinely used test for the assessment of male fertility; on the other hand, this test is not the most accurate, because seminal parameters within the proposed reference range do not promise fertility, nor do values outside these limits automatically indicate male infertility ( Serrano et al, 2022 ). Thus, more detailed analyses of the molecular mechanism(s) of testis and SPZ physiology are mandatory not only to expand knowledge of spermatogenesis but also, by identifying new molecular markers, to improve the standard assessment of male fertility through routine semen analysis.…”

“…Reproductive activity is one of the main attributes of living beings, as it is fundamental to species survival and genetic variability. To successfully achieve it, the production of good quality gametes, capable of fertilizing or being fertilized, is of primary importance ( Serrano et al, 2022 ). Male gamete differentiation occurs during spermatogenesis, a genetic and molecular program during which immature GC undergo several stages of cell division (mitotic and meiotic) and then, by intimate biochemical and morphological modification, to produce mature SPZ ( Dunleavy et al, 2019 ).…”

“…Indeed, many studies have described a progressive decline in fertility rates over the past 50 years, ranging from the 7%–8% observed in the early 1960s to the 15% we are witnessing today ( Levine et al, 2017 ; Levine et al, 2022 ). Although in many cases, the causes of male infertility can be attributed to well-known factors (genetic abnormalities, lifestyle), for most cases the etiology is still unknown (idiopathic infertility) ( Serrano et al, 2022 ). It should be considered that, among the factors affecting sperm quality, exposure to environmental pollutants is undoubtedly one of the main causes since, although male infertility is a worldwide health problem, its incidence is higher in more technologically advanced and developed countries ( Marić et al, 2021 ; Selvaraju et al, 2021 ).…”

Forkhead-associated phosphopeptide binding domain 1 (FHAD1) deficiency impaired murine sperm motility

“…Phosphorylation is the best-studied form of posttranslational modification in human spermatozoa ( Porambo et al, 2012 ). Global phosphorylation profiling efforts in spermatozoa from a range of species support key roles for such phosphorylation in the regulation of key activities including spermatogenesis, maturation, motility, and capacitation ( Serrano, Garcia-Marin & Bragado, 2022 ; Urizar-Arenaza et al, 2019 ). However, the precise molecular mechanisms that govern the motility of spermatozoa remain to be fully elucidated, as do the associated impacts on sperm quality.…”

“…Phosphorylation is vital for the regulation of sperm-related processes required for fertilization, including sperm motility, capacitation, and the acrosome reaction ( Serrano, Garcia-Marin & Bragado, 2022 ). The most common phosphorylation sites in mammalian proteins are serine and threonine residues, and many protein families capable of recognizing phosphorylated versions of these residues (pSer/pThr) have been identified to date ( Yaffe & Elia, 2001 ).…”