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Human Reproduction Update Feb 2022Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including... (Review)
Review
BACKGROUND
Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including cell differentiation and development. Emerging data indicate that autophagy is closely associated with male reproduction, especially the biosynthetic and catabolic processes of sperm. Throughout the fate of sperm, a series of highly specialized cellular events occur, involving pre-testicular, testicular and post-testicular events. Nonetheless, the most fundamental question of whether autophagy plays a protective or harmful role in male reproduction, especially in sperm, remains unclear.
OBJECTIVE AND RATIONALE
We summarize the functional roles of autophagy in the pre-testicular (hypothalamic-pituitary-testis (HPG) axis), testicular (spermatocytogenesis, spermatidogenesis, spermiogenesis, spermiation) and post-testicular (sperm maturation and fertilization) processes according to the timeline of sperm fate. Additionally, critical mechanisms of the action and clinical impacts of autophagy on sperm are identified, laying the foundation for the treatment of male infertility.
SEARCH METHODS
In this narrative review, the PubMed database was used to search peer-reviewed publications for summarizing the functional roles of autophagy in the fate of sperm using the following terms: 'autophagy', 'sperm', 'hypothalamic-pituitary-testis axis', 'spermatogenesis', 'spermatocytogenesis', 'spermatidogenesis', 'spermiogenesis', 'spermiation', 'sperm maturation', 'fertilization', 'capacitation' and 'acrosome' in combination with autophagy-related proteins. We also performed a bibliographic search for the clinical impact of the autophagy process using the keywords of autophagy inhibitors such as 'bafilomycin A1', 'chloroquine', 'hydroxychloroquine', '3-Methyl Adenine (3-MA)', 'lucanthone', 'wortmannin' and autophagy activators such as 'rapamycin', 'perifosine', 'metformin' in combination with 'disease', 'treatment', 'therapy', 'male infertility' and equivalent terms. In addition, reference lists of primary and review articles were reviewed for additional relevant publications. All relevant publications until August 2021 were critically evaluated and discussed on the basis of relevance, quality and timelines.
OUTCOMES
(i) In pre-testicular processes, autophagy-related genes are involved in the regulation of the HPG axis; and (ii) in testicular processes, mTORC1, the main gate to autophagy, is crucial for spermatogonia stem cell (SCCs) proliferation, differentiation, meiotic progression, inactivation of sex chromosomes and spermiogenesis. During spermatidogenesis, autophagy maintains haploid round spermatid chromatoid body homeostasis for differentiation. During spermiogenesis, autophagy participates in acrosome biogenesis, flagella assembly, head shaping and the removal of cytoplasm from elongating spermatid. After spermatogenesis, through PDLIM1, autophagy orchestrates apical ectoplasmic specialization and basal ectoplasmic specialization to handle cytoskeleton assembly, governing spermatid movement and release during spermiation. In post-testicular processes, there is no direct evidence that autophagy participates in the process of capacitation. However, autophagy modulates the acrosome reaction, paternal mitochondria elimination and clearance of membranous organelles during fertilization.
WIDER IMPLICATIONS
Deciphering the roles of autophagy in the entire fate of sperm will provide valuable insights into therapies for diseases, especially male infertility.
Topics: Autophagy; Humans; Infertility, Male; Male; Spermatids; Spermatogenesis; Spermatozoa
PubMed: 34967891
DOI: 10.1093/humupd/dmab043 -
International Journal of Molecular... Oct 2020Several studies proposed the importance of zinc ion in male fertility. Here, we describe the properties, roles and cellular mechanisms of action of Zn in spermatozoa,... (Review)
Review
Several studies proposed the importance of zinc ion in male fertility. Here, we describe the properties, roles and cellular mechanisms of action of Zn in spermatozoa, focusing on its involvement in sperm motility, capacitation and acrosomal exocytosis, three functions that are crucial for successful fertilization. The impact of zinc supplementation on assisted fertilization techniques is also described. The impact of zinc on sperm motility has been investigated in many vertebrate and invertebrate species. It has been reported that Zn in human seminal plasma decreases sperm motility and that Zn removal enhances motility. Reduction in the intracellular concentration of Zn during epididymal transit allows the development of progressive motility and the subsequent hyper activated motility during sperm capacitation. Extracellular Zn affects intracellular signaling pathways through its interaction with the Zn sensing receptor (ZnR), also named GPR39. This receptor was found in the sperm tail and the acrosome, suggesting the possible involvement of Zn in sperm motility and acrosomal exocytosis. Our studies showed that Zn stimulates bovine sperm acrosomal exocytosis, as well as human sperm hyper-activated motility, were both mediated by GPR39. Zn binds and activates GPR39, which activates the trans-membrane-adenylyl-cyclase (tmAC) to catalyze cAMP production. The NHE (Na/H-exchanger) is activated by cAMP, leading in increased pHi and activation of the sperm-specific Ca channel CatSper, resulting in an increase in [Ca], which, together with HCO, activates the soluble adenylyl-cyclase (sAC). The increase in [cAMP] activates protein kinase A (PKA), followed by activation of the Src-epidermal growth factor receptor-Pphospholipase C (Src-EGFR-PLC) cascade, resulting in inositol-triphosphate (IP) production, which mobilizes Ca from the acrosome, causing a further increase in [Ca] and the development of hyper-activated motility. PKA also activates phospholipase D1 (PLD1), leading to F-actin formation during capacitation. Prior to the acrosomal exocytosis, PLC induces phosphadidylinositol-4,5-bisphosphate (PIP) hydrolysis, leading to the release of the actin-severing protein gelsolin to the cytosol, which is activated by Ca, resulting in F-actin breakdown and the occurrence of acrosomal exocytosis.
Topics: Acrosome; Animals; Fertility; Humans; Male; Reproductive Techniques, Assisted; Sperm Capacitation; Sperm Motility; Spermatozoa; Zinc
PubMed: 33096823
DOI: 10.3390/ijms21207796 -
The Journal of Cell Biology Oct 2021Fertilization is defined as the union of two gametes. During fertilization, sperm and egg fuse to form a diploid zygote to initiate prenatal development. In mammals,... (Review)
Review
Fertilization is defined as the union of two gametes. During fertilization, sperm and egg fuse to form a diploid zygote to initiate prenatal development. In mammals, fertilization involves multiple ordered steps, including the acrosome reaction, zona pellucida penetration, sperm-egg attachment, and membrane fusion. Given the success of in vitro fertilization, one would think that the mechanisms of fertilization are understood; however, the precise details for many of the steps in fertilization remain a mystery. Recent studies using genetic knockout mouse models and structural biology are providing valuable insight into the molecular basis of sperm-egg attachment and fusion. Here, we review the cell biology of fertilization, specifically summarizing data from recent structural and functional studies that provide insights into the interactions involved in human gamete attachment and fusion.
Topics: Cell Biology; Fertilization; Humans; Membrane Fusion
PubMed: 34459848
DOI: 10.1083/jcb.202102146 -
Autophagy Jul 2021Spermiogenesis is the longest phase of spermatogenesis, with dramatic morphological changes and a final step of spermiation, which involves protein degradation and the...
Spermiogenesis is the longest phase of spermatogenesis, with dramatic morphological changes and a final step of spermiation, which involves protein degradation and the removal of excess cytoplasm; therefore, we hypothesized that macroautophagy/autophagy might be involved in the process. To test this hypothesis, we examined the function of ATG5, a core autophagy protein in male germ cell development. Floxed and mice were crossed to conditionally inactivate in male germ cells. In mutant mice, testicular expression of the autophagosome marker LC3A/B-II was significantly reduced, and expression of autophagy receptor SQSTM1/p62 was significantly increased, indicating a decrease in testicular autophagy activity. The fertility of mutant mice was dramatically reduced with about 70% being infertile. Sperm counts and motility were also significantly reduced compared to controls. Histological examination of the mutant testes revealed numerous, large residual bodies in the lumen of stages after their normal resorption within the seminiferous epithelium. The cauda epididymal lumen was filled with sloughed germ cells, large cytoplasmic bodies, and spermatozoa with disorganized heads and tails. Examination of cauda epididymal sperm by electron microscopy revealed misshapen sperm heads, a discontinuous accessory structure in the mid-piece and abnormal acrosome formation and loss of sperm individualization. Immunofluorescence staining of epididymal sperm showed abnormal mitochondria and acrosome distribution in the mutant mice. ATG5 was shown to induce autophagy by mediating multiple signals to maintain normal developmental processes. Our study demonstrated ATG5 is essential for male fertility and is involved in various aspects of spermiogenesis.: AKAP4: a-kinase anchoring protein 4; ATG5: autophagy-related 5; ATG7: autophagy-related 7; ATG10: autophagy-related 10; ATG12: autophagy-related 12; cKO: conditional knockout; DDX4: DEAD-box helicase 4; MAP1LC3/LC3/tg8: microtubule-associated protein 1 light chain 3; PBS: phosphate-buffered saline; PIWIL2/MILI: piwi like RNA-mediated gene silencing 2; RT-PCR: reverse transcription-polymerase chain reaction; SQSTM1/p62: sequestosome 1; TBC: tubulobulbar complexes; WT: wild type.
Topics: Acrosome; Animals; Autophagy; Autophagy-Related Protein 5; Blotting, Western; Epididymis; Fertility; Fluorescent Antibody Technique; Male; Mice; Mice, Knockout; Real-Time Polymerase Chain Reaction; Sperm Count; Spermatids; Spermatogenesis; Spermatozoa; Testis
PubMed: 32677505
DOI: 10.1080/15548627.2020.1783822 -
Cold Spring Harbor Perspectives in... Oct 2015Vertebrate reproduction requires a myriad of precisely orchestrated events-in particular, the maternal production of oocytes, the paternal production of sperm,... (Review)
Review
Vertebrate reproduction requires a myriad of precisely orchestrated events-in particular, the maternal production of oocytes, the paternal production of sperm, successful fertilization, and initiation of early embryonic cell divisions. These processes are governed by a host of signaling pathways. Protein kinase and phosphatase signaling pathways involving Mos, CDK1, RSK, and PP2A regulate meiosis during maturation of the oocyte. Steroid signals-specifically testosterone-regulate spermatogenesis, as does signaling by G-protein-coupled hormone receptors. Finally, calcium signaling is essential for both sperm motility and fertilization. Altogether, this signaling symphony ensures the production of viable offspring, offering a chance of genetic immortality.
Topics: Acrosome Reaction; Animals; Calcium Signaling; Cell Division; Cell Proliferation; Female; Fertilization; Humans; Male; Meiosis; Oocytes; Reproduction; Signal Transduction; Sperm Capacitation; Spermatogenesis; Spermatozoa; Stem Cells; Vertebrates; Zygote
PubMed: 26430215
DOI: 10.1101/cshperspect.a006064 -
In Vivo (Athens, Greece) 2022The process of fertilization includes sperm capacitation, hyperactivation, an acrosome reaction and the release of acrosome enzymes, membrane fusion and channel... (Review)
Review
The process of fertilization includes sperm capacitation, hyperactivation, an acrosome reaction and the release of acrosome enzymes, membrane fusion and channel formation, the release of the sperm nucleus, and gamete fusion. This process is closely related to the shape and vitality of the sperm, acrosome enzyme release, and the zona pellucida structure of the egg, as well as the opening and closing of various ion (e.g., calcium) channels, the regulation of signaling pathways such as cyclic adenosine monophosphate-protein kinase A, the release of progesterone, and the coupling of G-proteins. The interaction among multiple factors and their precise regulation give rise to multiple cascading regulatory processes. Problems with any factor will affect the success rate of fertilization. Recent studies have shown that with rapid societal development, the incidence of male infertility is increasing and occurs at younger ages. According to World Health Organization statistics, 15% of couples of childbearing ages have infertility problems, of which 50% are caused by male factors. Additionally, the cause of infertility cannot be identified in as many as 60% to 75% of male infertility patients. In this article, we review the research progress on the microregulation of fertilization and mechanisms underlying this process to identify causes and develop novel prevention and treatment strategies for male infertility.
Topics: Acrosome Reaction; Humans; Infertility, Male; Male; Semen; Sperm Capacitation; Spermatozoa
PubMed: 36099087
DOI: 10.21873/invivo.12926 -
Biological Reviews of the Cambridge... Apr 2020Mammalian sperm must spend a minimum period of time within a female reproductive tract to achieve the capacity to fertilize oocytes. This phenomenon, termed sperm... (Review)
Review
Mammalian sperm must spend a minimum period of time within a female reproductive tract to achieve the capacity to fertilize oocytes. This phenomenon, termed sperm 'capacitation', was discovered nearly seven decades ago and opened a window into the complexities of sperm-female interaction. Capacitation is most commonly used to refer to a specific combination of processes that are believed to be widespread in mammals and includes modifications to the sperm plasma membrane, elevation of intracellular cyclic AMP levels, induction of protein tyrosine phosphorylation, increased intracellular Ca levels, hyperactivation of motility, and, eventually, the acrosome reaction. Capacitation is only one example of post-ejaculatory modifications to sperm (PEMS) that are widespread throughout the animal kingdom. Although PEMS are less well studied in non-mammalian taxa, they likely represent the rule rather than the exception in species with internal fertilization. These PEMS are diverse in form and collectively represent the outcome of selection fashioning complex maturational trajectories of sperm that include multiple, sequential phenotypes that are specialized for stage-specific functionality within the female. In many cases, PEMS are critical for sperm to migrate successfully through the female reproductive tract, survive a protracted period of storage, reach the site of fertilization and/or achieve the capacity to fertilize eggs. We predict that PEMS will exhibit widespread phenotypic plasticity mediated by sperm-female interactions. The successful execution of PEMS thus has important implications for variation in fitness and the operation of post-copulatory sexual selection. Furthermore, it may provide a widespread mechanism of reproductive isolation and the maintenance of species boundaries. Despite their possible ubiquity and importance, the investigation of PEMS has been largely descriptive, lacking any phylogenetic consideration with regard to divergence, and there have been no theoretical or empirical investigations of their evolutionary significance. Here, we (i) clarify PEMS-related nomenclature; (ii) address the evolutionary origin, maintenance and divergence in PEMS in the context of the protracted life history of sperm and the complex, selective environment of the female reproductive tract; (iii) describe taxonomically widespread types of PEMS: sperm activation, chemotaxis and the dissociation of sperm conjugates; (iv) review the occurence of PEMS throughout the animal kingdom; (v) consider alternative hypotheses for the adaptive value of PEMS; (vi) speculate on the evolutionary implications of PEMS for genomic architecture, sexual selection, and reproductive isolation; and (vii) suggest fruitful directions for future functional and evolutionary analyses of PEMS.
Topics: Acrosome Reaction; Animals; Ejaculation; Male; Sperm Capacitation; Spermatozoa
PubMed: 31737992
DOI: 10.1111/brv.12569 -
Journal of Xenobiotics Jul 2022Infertility is a severe medical problem and is considered a serious global public health issue affecting a large proportion of humanity. Oxidative stress is one of the... (Review)
Review
Infertility is a severe medical problem and is considered a serious global public health issue affecting a large proportion of humanity. Oxidative stress is one of the most crucial factors involved in infertility. Recent studies indicate that the overproduction of reactive oxygen species (ROS) or reactive nitrogen species (RNS) may cause damage to the male and female reproductive systems leading to infertility. Low amounts of ROS and RNS are essential for the normal functioning of the male and female reproductive systems, such as sperm motility, acrosome reaction, interactions with oocytes, ovulation, and the maturation of follicles. Environmental factors such as heavy metals can cause reproductive dysfunction in men and women through the overproduction of ROS and RNS. It is suggested that oxidative stress caused by arsenic is associated with male and female reproductive disorders such as through the alteration in sperm counts and motility, decreased sex hormones, dysfunction of the testis and ovary, as well as damage to the processes of spermatogenesis and oogenesis. This review paper highlights the relationship between arsenic-induced oxidative stress and the prevalence of infertility, with detailed explanations of potential underlying mechanisms.
PubMed: 35893266
DOI: 10.3390/jox12030016 -
The Journal of Poultry Science Jul 2016Fertilization in animals that employ sexual reproduction is an indispensable event for the production of the next generation. A significant advancement in our... (Review)
Review
Fertilization in animals that employ sexual reproduction is an indispensable event for the production of the next generation. A significant advancement in our understanding of the molecular mechanisms of sperm-egg interaction in mammalian species was achieved in the last few decades. However, the same level of knowledge has not been accumulated for birds because of egg size and the difficulty in mimicking the physiological polyspermy that takes place during normal fertilization. In this review, we summarize the current understanding of sperm-egg interaction mechanism during fertilization in birds, especially focusing on sperm-egg binding, sperm acrosome reaction and the authentic sperm protease required for the hole formation on the perivitelline membrane. We explain that the zona pellucida proteins (ZP1 and ZP3) in the perivitelline membrane play important roles in sperm-egg binding, induction of the acrosome reaction as well as sperm penetration by digestion of sperm protease. We anticipate that a deeper understanding of avian fertilization will open up new avenues to create powerful tools for a myriad of applications in the poultry industries including the production of transgenic and cloned birds.
PubMed: 32908381
DOI: 10.2141/jpsa.0150183 -
Frontiers in Bioscience (Landmark... Mar 2019Mammalian fertilization that culminates by fusion of the male and female gametes is intricately regulated within the female reproductive tract. To become competent to... (Review)
Review
Mammalian fertilization that culminates by fusion of the male and female gametes is intricately regulated within the female reproductive tract. To become competent to fertilize an egg, the mammalian spermatozoa that enter the female reproductive tract must undergo a series of physiological changes, including hyperactivation, and capacitation. For reaching full competency, the acrosome, a specialized membrane-bound organelle that covers the anterior part of the sperm head, must undergo an acrosome reaction. For becoming competent to bind an ovum, and to penetrate the zona pellucida and cumulus, many sperm proteins are released in the course of the acrosome reaction. Ultimately, the acrosome binds to the oolemma and fusion of sperm and egg occurs. In this review, we outline current understanding of the roles and effects of some essential sperm proteins and their functions during fertilization in the female reproductive tract.
Topics: Acrosome Reaction; Animals; Antigens; Cell Adhesion Molecules; Female; Fertilins; Fertilization; Genitalia, Female; Humans; Hyaluronoglucosaminidase; Immunoglobulins; Male; Membrane Proteins; Mice; Receptors, Cell Surface; Spermatozoa; Zona Pellucida
PubMed: 30844709
DOI: 10.2741/4747