Sperm Ion Transporters and Channels in Human Asthenozoospermia: Genetic Etiology, Lessons from Animal Models, and Clinical Perspectives

Abstract

In mammals, sperm fertilization potential relies on efficient progression within the female genital tract to reach and fertilize the oocyte. This fundamental property is supported by the flagellum, an evolutionarily conserved organelle that provides the mechanical force for sperm propulsion and motility. Importantly several functional maturation events that occur during the journey of the sperm cells through the genital tracts are necessary for the activation of flagellar beating and the acquisition of fertilization potential. Ion transporters and channels located at the surface of the sperm cells have been demonstrated to be involved in these processes, in particular, through the activation of downstream signaling pathways and the promotion of novel biochemical and electrophysiological properties in the sperm cells. We performed a systematic literature review to describe the currently known genetic alterations in humans that affect sperm ion transporters and channels and result in asthenozoospermia, a pathophysiological condition defined by reduced or absent sperm motility and observed in nearly 80% of infertile men. We also present the physiological relevance and functional mechanisms of additional ion channels identified in the mouse. Finally, considering the state-of-the art, we discuss future perspectives in terms of therapeutics of asthenozoospermia and male contraception.

Reproductive Consequences of Electrolyte Disturbances in Domestic Animals

“…One of the most common causes of male infertility is asthenozoospermia, which is associated with a pathological reduction in sperm motility. Defects in transmembrane ion channels have been shown to cause asthenozoospermia [ 95 ]. Associated with the sperm cation channel (CatSper) is a protein channel located on the sperm plasma membrane.…”

“…Associated with the sperm cation channel (CatSper) is a protein channel located on the sperm plasma membrane. It is important in the process of sperm capacitation [ 95 ]. CatSper enables the influx of Ca 2+ ions into the sperm flagellum during capacitation and the mobility of the gametes [ 96 , 97 ].…”

“…It depends on cAMP and pH and is activated by progesterone. Genetic defects in CatSper have been shown to reduce sperm motility, reducing male fertility [ 95 , 100 ]. Furthermore, CatSper delivers these ions to the sperm flagellum as the main calcium channel of sperm [ 96 ].…”

The Role of Long Noncoding RNAs on Male Infertility: A Systematic Review and In Silico Analysis

“…Therefore, it is suggested that the interaction between ANO1-AS2 and ANO1 plays an important role in TAZ. This is not surprising, as ANO1 also interacts with other genes that play a role in male infertility, and especially sperm motility and morphology [ 58 ]. Furthermore, since mutations in the CFAP44 gene are associated with morphological defects in the sperm tail [ 56 ], Kamel et al (2022) [ 36 ] also studied the expression of CFAP44 and CFAP44-AS1 in patients with asthenoteratozoospermia.…”

Electrophysiology and Fluorescence Spectroscopy Approaches for Evaluating Gamete and Embryo Functionality in Animals and Humans

“…Moreover, by single-channel recording applied initially in sea urchin sperm plasma membrane, and then on spermatozoa of a series of animal models, the functional role of several types of ion channels was confirmed, including cations, such as K + and Ca 2+ , and anion (Cl − ) channels [ 64 ]. Clinical evidence also supports these indications, demonstrating that perturbation of ion channel activity due to human genetic alterations is significantly correlated with asthenozoospermia, a pathology characterized by reduced or absent sperm motility [ 65 ]. Along with motility, other steps involved in sperm activation, such as chemotaxis and acrosome reaction, are underpinned by ion channel activity.…”