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Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization (3rd Edition)

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (20 January 2026) | Viewed by 23348

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Dr. Jan Tesarik

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Guest Editor

MARGen (Molecular Assisted Reproduction and Genetics) Clinic, Calle Gracia, 36, 18002 Granada, Spain
Interests: human infertility; assisted reproduction; endocrinology; diagnosis; treatment; embryo developmental potential; sperm quality; oocyte quality
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Dear Colleagues,

The complex process of sperm development and maturation involves multiple interconnected steps that begin in the testis and result in fertility acquisition inside the male genital tract as well as the female genital tract. The sperm then must cope with the active immune system and particular tract homeostasis. A special segment, the sperm reservoir, stores the sperm cells until they are released and move toward the fertilization site.

This Special Issue aims to cover the crucial molecular events and mechanisms in sperm development. The scope includes research on sperm cell physiology and components in the seminal plasma and/or in the female, allowing for the realization of the full fertilization of sperm, including extracellular vesicles. Thus, in vitro and in vitro studies aiming at unraveling new molecular determinants of acquiring the full functionality of sperm are welcome.

Dr. Jan Tesarik
Guest Editor

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Keywords

sperm physiology
seminal plasma
extracellular vesicles
reproduction
spermatogenesis
capacitation
fertility

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Published Papers (5 papers)

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Research

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21 pages, 5508 KB

Open AccessArticle

Autophagy-Related Proteins Influence Mouse Epididymal Sperm Motility

by Lorena Rodríguez-Páez, Jonathan J. Magaña, Charmina Aguirre-Alvarado, Verónica Alcántara-Farfán, Germán Chamorro-Cevallos, José Melesio Cristóbal-Luna, Erika Rosales-Cruz, Elba Reyes-Maldonado, Guadalupe Elizabeth Jiménez-Gutiérrez and Joaquín Cordero-Martínez

Int. J. Mol. Sci. 2025, 26(24), 11895; https://doi.org/10.3390/ijms262411895 - 10 Dec 2025

Viewed by 640

Abstract

Autophagy is an intracellular process that recycles and degrades cytoplasmic components, including organelles and macromolecules, to provide energy and basic components for cell survival, maintain cellular homeostasis, and avoid self-damage. It is currently not fully known if mouse sperm undergoes the autophagy process, nor is the subcellular distribution, protein levels of autophagy-related proteins, and the biological role of autophagy in epididymal mouse sperm physiology fully understood. We aimed to investigate key autophagy markers, including LC3 (microtubule-associated protein 1A/1B-light chain 3), p62/SQSTM1 (Sequestosome 1), and mTOR (mechanistic Target of Rapamycin), in epididymal mouse sperm under capacitation (Cap) or non-capacitation (NC) conditions. Furthermore, we evaluated the possible role of these autophagy-related proteins on sperm viability, motility, intracellular pH (pHi), intracellular calcium concentrations [Ca²⁺]i, mitochondrial membrane potential, and acrosome reaction (AR) induction in the presence or absence of chloroquine (CQ), K67, and rapamycin. Our results suggest a dynamic re-localization of the autophagy-related proteins LC3, p62/SQSTM1, and mTOR under capacitation conditions. Moreover, treatment with specific autophagy inhibitors, such as CQ and K67, resulted in decreased LC3-II and p62/SQSTM1 protein levels. Additionally, rapamycin did not increase mTOR levels. Interestingly, treatment with these inhibitors also resulted in decreased motility, reduced mitochondrial membrane potential and hindered AR induction without affecting sperm viability. Overall, the presence and dynamic re-localization of LC3, p62/SQSTM1, and mTOR suggest that mouse epididymal sperm could perform initial steps of autophagy under capacitation conditions, and results of the pharmacological treatment could be associated with an important role of these autophagy-related proteins in sperm motility and AR induction. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization (3rd Edition))

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12 pages, 1157 KB

Open AccessArticle

Sperm rDNA Copy Number and Methylation Are Associated with Male-Factor Infertility

by Alina Michler, Sarah Kießling, Jana Durackova, Thomas Hahn, Martin Schorsch and Thomas Haaf

Int. J. Mol. Sci. 2025, 26(21), 10657; https://doi.org/10.3390/ijms262110657 - 1 Nov 2025

Cited by 1 | Viewed by 925

Abstract

Both absolute and presumably active rDNA (with a hypomethylated promoter region) copy number (CN) in the haploid human sperm genome are highly variable among individuals. Using a combination of droplet digital PCR and deep bisulfite sequencing, we have quantified absolute and presumably active rDNA CN in sperm samples (N = 190) with normal (NSPs) vs. abnormal semen parameters (ASPs), as well as in samples leading or not leading to a clinical pregnancy. ASP samples had a significantly lower presumably active CN (104 ± 31) than normozoospermic samples (115 ± 31). The loss of presumably active rDNA copies is explained by an increased promoter methylation (13.9% in ASP vs. 12.1% in NSP). When correcting for confounding factors, most importantly semen quality, samples not leading to a clinical pregnancy after IVF/ICSI displayed a significantly lower absolute (225 ± 51) and presumably active CN (103 ± 30) than samples with pregnancy (249 ± 62 and 115 ± 31, respectively). This between-group difference was most noticeable in normozoospermic males: absolute CN 220 ± 54; presumably active CN 107 ± 32 in samples without pregnancy and absolute CN 246 ± 63; presumably active CN 120 ± 28 in samples with pregnancy. We propose that absolute/active rDNA CN in sperm is a modulating factor contributing to idiopathic male infertility. In NSP samples, presumably active CN increases with absolute CN, which may have a positive impact on fertility and ART outcome. Our results suggest that approximately 60 active sperm rDNA copies are sufficient to establish a pregnancy. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization (3rd Edition))

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20 pages, 4098 KB

Open AccessCommunication

Nor1 and Mitophagy: An Insight into Sertoli Cell Function Regulating Spermatogenesis Using a Transgenic Rat Model

by Bhola Shankar Pradhan, Deepyaman Das, Hironmoy Sarkar, Indrashis Bhattacharya, Neerja Wadhwa and Subeer S. Majumdar

Int. J. Mol. Sci. 2025, 26(18), 9209; https://doi.org/10.3390/ijms26189209 - 20 Sep 2025

Viewed by 1355

Abstract

Male infertility is a global health concern, and many cases are idiopathic in nature. The development and differentiation of germ cells (Gcs) are supported by Sertoli cells (Scs). Differentiated Scs support the development of Gcs into sperm, and hence, male fertility. We previously reported on a developmental switch in Scs around 12 days of age onwards in rats. During the process of the differentiation of Scs, the differential expression of mitophagy-related genes and its role in male fertility are poorly understood. To address this gap, we evaluated the microarray dataset GSE48795 to identify 12 mitophagy-related hub genes, including B-Cell Leukemia/Lymphoma 2 (Bcl2) and FBJ murine osteosarcoma viral oncogene homolog (Fos). We identify Neuron-derived orphan receptor 1 (Nor1) as a potential mitophagy-related gene of interest due to its strong regulatory association with two hub genes, Bcl2 and Fos, which were differentially expressed during Sc maturation. To validate this finding, we generated a transgenic rat model with the Sc-specific knockdown of Nor1 during puberty. A functional analysis showed impaired spermatogenesis with reduced fertility in these transgenic rats. Our findings suggest that Nor1 may be an important mitophagy-related gene regulating the function of Scs and thereby regulating male fertility. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization (3rd Edition))

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17 pages, 3413 KB

Open AccessArticle

Alpha4 Na,K-ATPase Localization and Expression Are Dynamic Aspects of Spermatogenesis and in Sperm Incubated Under Capacitating Conditions

by David Milewski and Paul F. James

Int. J. Mol. Sci. 2025, 26(5), 1817; https://doi.org/10.3390/ijms26051817 - 20 Feb 2025

Cited by 3 | Viewed by 1353

Abstract

Utilizing high-resolution microscopy in conjunction with a new antibody highly specific for rat alpha4 Na,K-ATPase, we describe changes in alpha4 expression during spermatogenesis and in sperm incubated under capacitating and noncapacitating conditions. Immunohistochemical analyses showed alpha4 expression at low levels in spermatogonia and in pachytene spermatocytes. Alpha4 then becomes highly expressed on round spermatids and the midpiece of elongated spermatozoa within the seminiferous tubules. In noncapacitating conditions, alpha4 was confined mainly to the flagellum of mature sperm; however, under capacitating conditions, sperm acquired intense alpha4 staining along the acrosomal region of the sperm head. To visualize the precise localization of alpha4 in the sperm head, we performed an ultrastructural analysis using immuno-scanning electron microscopy. Under capacitating conditions, sperm exhibited alpha4 staining along the dorsal surface of the sperm head associated with the acrosome. In addition, after 4 h of incubation in motility buffer, we observed an increase in alpha4 protein in sperm that could be blocked with chloramphenicol, a mitochondrial-type ribosome inhibitor. These findings demonstrate that both the localization and expression level of alpha4 Na,K-ATPase are dynamic aspects of sperm maturation and suggest that sperm motility and capacitation may be supported by these changes to the location and amount of this protein. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization (3rd Edition))

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Review

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23 pages, 1309 KB

Open AccessReview

Lifestyle and Environmental Factors Affecting Male Fertility, Individual Predisposition, Prevention, and Intervention

by Jan Tesarik

Int. J. Mol. Sci. 2025, 26(6), 2797; https://doi.org/10.3390/ijms26062797 - 20 Mar 2025

Cited by 32 | Viewed by 17983

Abstract

Current lifestyles bring about an increasing prevalence of unhealthy habits that can negatively affect male fertility. Cigarette smoking, alcohol intake, stress, inadequate physical activity, an unequilibrated diet leading to obesity, and use of mobile telephones and portable electronic devices can affect the male reproductive system through multiple mechanisms. Moreover, the modern man is often exposed to environmental factors independent of his will, such as air pollution, exposure to heat or toxicants in his workplace, or the presence of harmful chemicals in food, beverages, agricultural and industrial products, etc. The susceptibility to these factors depends on genetic and epigenetic predisposition, potentially present systemic disease and medication, and local affections of the genitourinary system. The multifaceted nature of both the causative factors and the susceptibility background makes the resulting fertility disturbance highly individual and variable among different men exposed to the same conditions. This paper critically reviews the current knowledge of different causative and susceptibility factors with a special attention to the molecular mechanisms of their action. Finally, strategies for the prevention of abnormalities due to lifestyle and environmental factors and available treatment modalities for already-present abnormalities are exposed. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Sperm Development, Maturation, and Fertilization (3rd Edition))

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