GLOBAL ANDROLOGY FORUM
GLOBAL ANDROLOGY FORUM
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Causes and Consequences of Sperm Mitochondrial Dysfunction.
Article #43: “Causes and Consequences of Sperm Mitochondrial Dysfunction.”
Authors: Damayanthi Durairajanayagam, Dipty Singh, Ashok Agarwal, and Ralf Henkel,
Andrologia, 2021;53(1): e13666. DOI: 10.1111/and.13666
CAPSULE
Contributors: Georgia Kakourou, MSc, PhD (Greece), and
Athanasios Zachariou, MD, PhD (Greece)
Commentary:
Prelude:
The article by Durairajanayagam et al. (2021) discusses the multifunctional role of mitochondria. It provides a comprehensive overview of mitochondrial origin, structure, function, and dynamics, including the unique features of mitochondrial DNA (mtDNA), before exploring their involvement in sperm function and male fertility. Mitochondria are involved in the generation of energy in the form of ATP, the regulation of homeostasis, apoptosis, and signaling through reactive oxygen species (ROS), while, particularly relevant to sperm function, mitochondria provide energy for processes like sperm motility, hyperactivation, capacitation, acrosome reaction, and fertilization.
Main Highlights:
- a) defects in mitochondrial ultrastructure in ejaculated sperm impact sperm motility and integrity and are associated with asthenozoospermia.
- b) oxidative stress, triggered by mitochondrial ROS generation, damages sperm, leading to apoptosis, resulting in loss of motility and oxidative DNA damage (oxidative stress is discussed in management special reports #29 and #35),
- c) mitochondrial membrane potential is correlated with sperm quality (motility and DNA integrity); sperm with low mitochondrial membrane potential (MMP) exhibit lower quality and fertilization rates during in vitro fertilization.
- d) alterations in sperm mitochondrial DNA copy number and mtDNA variants, single nucleotide polymorphisms and haplogroups impact semen quality, reduce sperm functionality and lower odds of fertilization in an ART setting.
- e) other factors, like varicocele and exposure to electromagnetic fields, further exacerbate mitochondrial dysfunction, affecting sperm metabolism.
The authors suggest that addressing mitochondrial dysfunction can be crucial for improving the management of male infertility.
Our Insight:
Mitochondria have generally been investigated as crucial players in reproduction. The potential utility of mtDNA copy number and integrity as a biomarker of sperm quality must overcome challenges in the variability of methodologies used and the variability of mitochondrial characteristics among individuals. In the context of preimplantation genetic testing, mtDNA quantification has been investigated on trophectoderm cells obtained by embryo biopsy for nearly ten years as a marker of implantation potential, performed alongside embryo aneuploidy testing to improve ART success, but with contradicting results. With regards to male infertility, mtDNA variants may lead to or be associated with reduced sperm motility, function, and impaired fertilization. Mitochondrial replacement therapy has also been employed in the field of assisted reproduction as a means to avoid the transmission of mtDNA disease but also as an add-on to fertility treatment, mainly to improve oocyte quality in women with difficulties conceiving. Despite clinical application, there seems insufficient evidence to support the benefit of this approach in achieving pregnancy.
It is anticipated that incorporating a combination of the above-mentioned mitochondria-related biomarkers (for example, measurement of mitochondrial abundance, morphology, mitochondrial membrane potential, generation of ATP, and ROS production) in the assessment of sperm health may provide a more comprehensive evaluation of male fertility, particularly in cases where traditional assessments yield inconclusive results. As research progresses, the above may become of clinical use. Other ongoing research areas may involve sperm epigenetics (please refer to management special report #25) and the potential crosstalk between sperm
mitochondria and non-coding RNAs in the nuclear genome. Finally, future studies may also consider using techniques for editing the mitochondrial genome.
Future Research:
The authors propose areas of future research which need to be explored. These include understanding the mechanisms and implications involved in the selective degradation of paternal mitochondria in the preimplantation embryo, elucidating the limited ability of spermatozoa for DNA repair, and the impact of advancing age and the mechanisms involved in sperm ageing.
Final Thoughts:
This article has been very inspiring, defining new research aims and underlining the need to achieve a deeper molecular understanding of the role of mitochondria in reproduction. This will support targeted and tailored interventions for improving the management of male infertility. Improved management may include advances in reproductive assessment for early identification of infertile males, personalized treatment (e.g. use of antioxidants), suitable ART protocols and laboratory conditions, depending on the mitochondrial dysfunction. Our advancing knowledge will eventually support better counselling for infertile couples.
Key Takeaways: (Contributor: Ashok Agarwal)
The article highlights mitochondria's crucial role in sperm functionality and its link to male infertility, stressing the importance of mitochondrial health for sperm motility, DNA integrity, and overall semen quality. It suggests that assessing mitochondrial membrane potential could improve infertility diagnoses. However, unresolved issues remain, including the mechanisms of paternal mitochondrial DNA elimination, sperm's DNA repair capacity, mitochondrial DNA's role as a fertility marker, aging's impact on fertility, and the diagnostic potential of mitochondrial characteristics, indicating a need for further research in this sphere.
My Personal Viewpoint on Sperm Mitochondrial Dysfunction:
Dr. Georgia Kakourou responds to the questions by Ashok Agarwal
Q1: How does mitochondrial dysfunction contribute to asthenozoospermia and affect sperm motility and integrity?
A1: Sperm mitochondrial dysfunction contributes to asthenozoospermia largely due to the insufficient production of energy, which is needed for a functioning flagellum. Mitochondrial dysfunction may also lead to increased production of ROS affecting the structural and functional integrity of the sperm tail and midpiece and may also trigger apoptosis, reducing sperm count and overall sperm quality. In practice, spermatozoa from individuals with asthenozoospermia indicate reduced sperm movement, reduced mitochondrial membrane potential (MMP), defects in mitochondria ultrastructure and higher rates of apoptosis compared to fertile controls.
Q2. What is the impact of mitochondrial DNA (mtDNA) mutations, deletions, and variations on male fertility and semen quality?
A2: Variations in mtDNA (point mutations, rearrangements, duplications, deletions) may impact semen quality/function due to:
1) compromised energy production (mtDNA partially encodes for OXPHOS-related proteins)
2) increased ROS production
3) abnormalities in spermatogenesis, affecting sperm count, morphology and quality.
Higher levels of mtDNA variations have been detected in infertile patients of varying phenotypes (e.g. asthenozoospermia, oligoasthenozoospermia, obstructive azoospermia), while mtDNA integrity has been correlated to sperm fertilization rate. Studies have also associated elevated mtDNA copy number with poor sperm quality.
Q3. How does oxidative stress, induced by mitochondrial reactive oxygen species (ROS) generation, lead to sperm apoptosis and DNA damage?
A3: Mitochondrial ROS generation can initiate a cascade of events leading to
1) lipid peroxidation, that damages the structural integrity of the sperm membrane,
2) oxidation of proteins within the sperm causing structural and functional alterations,
3) excessive DNA damage
4) mitochondrial dysfunction.
These collectively contribute to the release of pro-apoptotic factors and the activation of the intrinsic apoptotic pathway. The release of cytochrome c from damaged mitochondria activates caspases, leading to programmed cell death and DNA fragmentation, overall compromising sperm quality and fertility.
Q4. In what ways does mitochondrial membrane potential (MMP) serve as an indicator of sperm quality and fertility potential?
A4: Mitochondrial Membrane Potential (MMP) serves as an indicator of sperm quality by reflecting the functional status of mitochondria. High MMP levels indicate efficient energy production, which is crucial for optimal sperm motility and functionality. Healthy mitochondria with an intact MMP indicate better resistance to oxidative stress and mitochondrial dysfunction. Additionally, MMP is linked to mitochondrial DNA integrity and fertilization potential, making it a valuable marker for assessing fertility and overall sperm health (count, morphology, motility, and viability).
Q5. How do alterations in mitochondrial function affect ATP production and its consequences for sperm function, including capacitation and the acrosome reaction?
A5: Sperm mitochondria provide energy in the form of ATP. ATP supports the required changes in sperm plasma membrane composition and functionality during capacitation, as well as fusion of the sperm plasma membrane and the outer acrosomal membrane and subsequent release of enzymes to facilitate penetration of the oocyte, during the acrosome reaction. Mitochondria also produce ROS, which are involved in the above processes. When mitochondria are dysfunctional, ATP levels are reduced, while elevated levels of ROS become harmful (oxidative stress) and further impair mitochondrial function, exacerbating ATP depletion and negatively impacting sperm function and competence.
Georgia Kakourou, MSc, PhD: Short Biography
Georgia Kakourou, MSc, PhD
Molecular Biologist-Geneticist
National and Kapodistrian University of Athens
Laboratory of Medical Genetics,
Choremio Research Laboratory, St. Sophia’s Children’s Hospital
Athens, Greece
E-mail: gkakourou@med.uoa.gr
Dr. Georgia Kakourou
is a Molecular Biologist-Geneticist, working in Preimplantation Genetic Testing diagnostics since 2002, and currently a clinical scientist and Scientific Associate at the Laboratory of Medical Genetics of the University of Athens (UoA), Greece. She obtained her MSc and PhD in Human Genetics from University College London, UK and between 2002‐2009 worked at the “UCL Centre for PGD” undertaking mainly PGT for monogenic disorders. Since then, she continues to be involved in PGT at UoA, as well as studies and activities in the field of reproductive genetics. Since 2013, she has been actively involved in the Steering Committee of the Special Interest Group “Reproductive Genetics” of the European Society of Human Reproduction and Embryology (ESHRE) as a member, deputy, coordinator, past-coordinator, and currently basic science officer. She has academic teaching and research activities at UoA and serves as a reviewer for several journals in the reproductive genetics field.
My Personal Viewpoint on Sperm Mitochondrial Dysfunction
Dr. Athanasios Zachariou responds to the questions by Ashok Agarwal
Q1: What are the implications of mtDNA copy number variations and integrity for assessing male fertility?
A1: The integrity of mtDNA is crucial for assessing male fertility due to its impact on sperm motility. Mutations, deletions, and duplications in mtDNA can compromise semen quality, leading to asthenozoospermia or oligoasthenozoospermia. Sperm motility is directly correlated with the functionality of oxidative phosphorylation (OXPHOS) pathways, which are partially encoded by mtDNA. Higher levels of deleted mtDNA have been observed in spermatozoa with poor motility and morphology leading to reduced sperm functionality and lower odds of fertilization in an ART setting.
Q2. How does the mitochondrial genome differ from the nuclear genome, and what are the clinical implications of these differences for male infertility?
A2: The mitochondrial genome differs from the nuclear genome in several ways. Firstly, mitochondrial genes are solely inherited from the mother and don't adhere to Mendelian inheritance. Secondly, while the mitochondrial genome typically maintains homoplasmy, heteroplasmy can exist within a cell. Thirdly, the mutation rate of mitochondrial DNA is considerably higher than that of nuclear DNA. These distinctions have clinical implications for male infertility as mutations in mitochondrial DNA can impact sperm function and fertility potential, contributing to male infertility issues.
Q3. What role does the selective degradation of paternal mitochondria play in the fertilization process and the maintenance of mtDNA homoplasmy?
A3: The selective degradation of paternal mitochondria in the fertilized egg ensures maternal inheritance of mtDNA, maintaining homoplasmy. This process, coupled with oogenesis-related mechanisms like replication from a single or very few template mtDNA, establishes homoplasmy in the oocyte. By reducing mtDNA copy number, the variability inmtDNA transmission is minimized, preventing the accumulation of mutated genomes and potential mitochondrial dysfunction.
Q4. How does the environment, including exposure to electromagnetic fields and varicocele, influence mitochondrial function and male fertility?
A4: The environment, including exposure to electromagnetic fields and varicocele, can influence mitochondrial function and male fertility by inducing oxidative stress. Both factors can lead to increased mitochondrial ROS production in spermatozoa, resulting in lipid peroxidation, impaired sperm motility, and DNA damage. Additionally, varicocele has been associated with under expression of essential mitochondrial proteins, contributing to metabolic dysregulation and sperm dysfunction.
Q5. What future research directions are proposed for understanding the role of mitochondria in sperm function and male fertility, and how might these findings translate into clinical practice?
A5:
Future research directions include investigating mechanisms of paternal mitochondrial genome transmission and degradation, exploring spermatozoa's DNA repair response to oxidative stress, and assessing mtDNA integrity as a biomarker of sperm quality. These findings may translate into clinical practice by potentially utilizing sperm mitochondrial characteristics as biomarkers for sperm function and fertilizing capacity.
Athanasios Zachariou, MD, PhD: Short Biography
Athanasios Zachariou, MD, PhD, FEBU
Assistant Professor
Urology Department
Ioannina University
Ioannina, Greece
Email:
Dr. Athanasios Zachariou is an Assistant Professor in the Urology Department of Ioannina University. He is the President of the Coordinating Committee of Andrology and Infertility of the Hellenic Urological Association. He holds a master’s degree in “Management of Health Units” (Open University of Cyprus, 2014) and a PhD degree from Aristotle University of Thessaloniki (2004), specialized on neurourology and the functional urology of the lower urinary tract. Athanasios has been a Fellow of the European Board of Urology (FEBU) since 1998. He is a board member of the EAU Section of Outpatient and Office Urology (ESUO), an ex-officio board member of the EAU Section of Female and Functional Urology (ESFFU), and an associate member of the European Section of Andrological Urology (ESAU). He has been awarded for his research work eight times (four times at European Urology Conferences). His research and clinical activity focus on male infertility, male and female sexual function, and the pathophysiology of the lower urinary tract system.