Spermatozoon and mitochondrial DNA (2024)

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Reprod Med Biol. 2002 Sep; 1(2): 41–47.

Published online 2002 Dec 11. doi:10.1046/j.1445-5781.2002.00007.x

PMCID: PMC5904680

PMID: 29699072

Shuji Hirata,¹ Kazuhiko Hoshi,¹ Tomoko Shoda,¹ and Tadashi Mabuchi²

Author information Article notes Copyright and License information PMC Disclaimer

Abstract

In eukaryotic cells, mitochondria are the major site of ATP production, which is achieved through the electron‐transport chain and oxidative phosphorylation, according to the energy demand. Mitochondria contain their own genome (mitochondrial DNA, mtDNA) on which a limited number of genes are encoded. In the human sperm, mitochondria helically wrap the midpiece of the tail and supply the energy for the driving force of motility. While various mutations in mtDNA in somatic cells are found to be associated with a wide spectrum of diseases, it is also reported that the abnormal mtDNA causes astenozoospermia and male infertility. At fertilization, the paternal mitochondria and mtDNA are rapidly degraded early in embryogenesis, thus, only maternal mtDNA is transmitted to the descendant. We briefly review here the basic characteristics of mtDNA and its maternal transmission during fertilization, as well as male infertility. (Reprod Med Biol 2002; 1: 41–47)

Keywords: human, mitochondrial DNA, spermatozoon

INTRODUCTION

THE SPERMATOZOON CONTAINS approximately 50–75 pieces of mitochondria in its midpiece.¹ The structure and function of the sperm mitochondria are essentially similar to mitochondria in somatic cells. The sperm mitochondria produce energy for the movement of the sperm. The sperm mitochondria, as well as the mitochondria in the somatic cells, contain its own DNA (mitochondrial DNA; mtDNA). In the present review, we will briefly summarize: (i) the basic structure and function of the mitochondria; (ii) the primary structure and characteristics of the mtDNA; (iii) the mutations in the mtDNA; and (iv) the mechanism of maternal inheritance of the mtDNA for the basic understanding about the sperm mitochondria. We also recommend readers to refer to recent reviews and books listed below², ³, ⁴, ⁵, ⁶, ⁷, ⁸ for more comprehensive information on these fields.

MITOCHONDRIA AND MITOCHONDRIAL DNA

Origin of mitochondria

THE MITOCHONDRIA ARE semiautonomous organelles found in almost all eukaryotic cells. Although the origin of the mitochondria is still controversial, it is a widely accepted hypothesis that the origin of mitochondria is the endosymbiosis of the ancestors of eukaryotic cells and α‐proteobacteria.⁹ The ancestral eukaryotic cell was originally an aerobic organism in which oxygen could not only be used for energy production, but it also acted as a ‘poison’. However, during the endosymbiotic process with the oxygen‐metabolizing α‐proteobacteria, the ancestral eukaryotic cell acquired the capacity of using oxygen for energy production through oxidative phosphorylation (OXPHOS). The OXPHOS is much more efficient at producing energy than anaerobic glycolysis (one molecule of glucose yields two molecules of ATP (adenosine triphosphate) by glycolysis, but 36 molecules of ATP through OXPHOS).¹⁰ Consequently, the eukaryotic organism that obtained the mitochondria has gained an enormous selective advantage to prosper.

Basic structure and function of mitochondria

The mitochondria are a cytoplasmic organelle that can propagate only by the fission of the pre‐existing mitochondria. The organelle is composed of double membranes: an outer membrane and an inner membrane. These two membranes divide the mitochondria into two compartments: the space surrounded by the inner membrane, which is called the matrix, and the space between the outer and inner membranes, which is called the intermembrane space. The outer membrane is thought to originate from the invagin*ted host plasma membrane, and this membrane is permeable to molecules whose molecular weight is almost less than 10kDa.¹¹ In contrast, the inner membrane is highly impermeable and all molecules and ions require specific translocators to enter the matrix. As the inner membrane forms a deep fold into the matrix, called the cristae, the surface area of the inner membrane is larger than that of the outer one. On the inner membrane, four distinct membrane‐spanning complexes, termed the respiratory chain complexes, NADPH (reduced nicotinamide adenine dinucleotide phosphate) dehydrogenase, succinate dehydrogenase, cytochrome bc1, and cytochrome c oxidase (complexes I, II, III and IV, respectively) as well as the ATP synthase (complex V) are localized. These respiratory chain (electron transport chain) complexes comprise the OXPHOS necessary to generate the ATP. In the matrix, the enzymes involved in the citric acid cycle, the oxidation of the fatty acid and amino acids, various intermediate metabolic substrates, newly synthesized ATP, the mitochondrial DNA (mtDNA) and mitochondrial ribosomes are present.

The mitochondria change their shape, move in the cytoplasm and undergo branching as well as fusion and fission. During cell division, the mitochondria propagate by fission of the pre‐existing mitochondria. The number of mitochondria is demonstrated to be regulated according to the energy demand in the individual tissues and cells, although the mechanism of this regulation is still obscure. In contrast, the excess mitochondria are digested by the lysosome or proteasome.

In addition to the energy production by the OXPHOS, the mitochondria are involved in the metabolism of amino acids, fatty acids, folic acids, uric acids and nucleotides, and in the regulation of the intracellular Ca²⁺ ion concentration. Also, the release of the cytochrome c, which is an intermembranous protein involved in the OXPHOS, from the intermembrane space is demonstrated to be one of the central pathways of apoptosis (the program cell death).¹² Thus, the mitochondria are involved not only in the survival of the cells through energy production and metabolism of various matters, but also in cell death through apoptosis.

Structure and gene expression of mitochondrial DNA

The human mitochondrial genome comprises a circular, histone‐free chromosome of 16569base pairs of DNA (mtDNA),¹³ which is found to occur as one or more copies in every mitochondrion. Each strand of the human mtDNA is classified into the H (heavy)‐strand and L (light)‐strand according to the difference of the ‘weight’; each strand is separated by an alkaline‐CsCl gradient centrifugation¹⁴ (Fig.1). The mtDNA encodes the 13 proteins that are parts of the subunits of the respiratory chain complexes: complexes I, III, IV and complex V (ATP synthase; Table1).¹⁵ The mtDNA also encodes two mitochondrial ribosomal RNAs (rRNAs) and the 22 transfer RNAs (tRNAs) that are used for protein synthesis in the organelle. The genes for these proteins and RNAs are tightly packed with no introns on the circular DNA (Fig.1).

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Table 1

Respiratory chain complexes I–V encoded by mitochondrial genome ¹⁵

Complex	No. subunits	No. subunits encoded on mitochondrial genome
I NADPH dehydrogenase	>41	7
II Succinate dehydrogenase	4	0
III Cytochrome bc1	11	1
IV Cytochrome c oxidase	13	3
V ATP synthase	14	2

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ATP, adenosine triphosphate.

The expression of mtDNA genes is not regulated by the individual promoter of the individual gene but by a promoter on the H‐strand (promoter for H‐strand transcription; HSP (P_H)) and one on the L‐strand (promoter for L‐strand transcription; LSP (P_L); Fig.2, middle panel). Both of the primary transcripts from the H‐ and L‐strands contain multiple genes.¹⁴ These transcripts are generated after activation of HSP and LSP by a transcription factor, mtTFA.¹⁶ The rRNAs and tRNAs are generated by the cleavage of the primary transcripts. The mature mRNAs for the respiratory chain complexes are also generated by poly A addition to the processed primary transcripts. The two distinct longer and shorter primary transcripts are generated from the H‐strand by the alternative transcription termination by the use of the transcription termination factor (mTERF: human mitochondrial transcription termination factor¹⁷). The levels of rRNAs are regulated by the ratio of the levels of these two H‐strand transcripts.¹⁸ It should be noted that some codons that are used in mtDNA genes are different from those used in the nuclear DNA (universal codon); that is, the codon UGA corresponding to the stop codon in the nuclear DNA is used for tryptophan in the mtDNA genes.

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Figure 2

Mechanism of the transcription and a strand‐asynchronous, asymmetric mechanism of the replication of mitochondria DNA. HSP, promoter for H‐strand transcription (P _H); LSP, promoter for L‐strand transcription (P_L); O_H, origin of H‐strand replication.¹⁶

The vast majority of the mitochondrial proteins essential for the maintenance and regulation of the function of the organelle; that is, the structural proteins, parts of the subunits of the respiratory chain complexes, the mitochondrial DNA and RNA polymerases, the transcription‐, translation‐ and transcription termination factors, the RNA processing enzymes, the mitochondrial ribosomal proteins, the aminoacyl tRNA synthases, and many other proteins are encoded on the nuclear genome. These proteins are synthesized in the cytoplasm and transported into the mitochondria through the translocators, which are composed of the integral membrane multisubunit complexes, with the help of the cytoplasmic, and mitochondrial chaperones.¹⁹, ²⁰, ²¹ The mitochondrial and nuclear genes are thought to be coordinately expressed according to energy demands.

Characterization of mitochondrial DNA

Replication mechanism of mitochondrial DNA

It has been widely accepted for a long time that mammalian mtDNA is replicated by a strand‐asynchronous, asymmetric mechanism.²² However, it was revealed that there is an alternative replication mechanism; that is, coupled leading‐ and lagging‐strand, unidirectional replication.²³, ²⁴ It is considered that these two modes of mtDNA replication operate under different conditions.

Briefly, the H‐strand replication in the former mechanism takes place at the origin of the H‐strand replication (O_H), and proceeds in a clockwise direction in the middle panel of Fig.2 using the L‐strand as a template. Since the first 1000 or more base pairs of the new H‐strand remain bound to the L‐strand template, the parental H‐strand is displaced and temporarily forms a single‐stranded loop structure, termed the D (displacement)‐loop, at the early stage of replication (Fig.2 upper panel). When two‐thirds of the new H‐strand is generated, the synthesis of the new L‐strand initiates from the origin of the L‐strand replication (O_L) in a counter‐clockwise direction in the middle panel of Fig.2 using the H‐strand as a template.

In the latter mechanism, mtDNA replication is initiated unidirectionally near O_H. So far, the strand‐asynchronous mechanism is predominantly used for maintaining a constant mtDNA copy number, while strand‐coupled mtDNA synthesis dominates the recovery from a low mtDNA copy number. It remains to be elucidated which mode is predominant in spermatogenesis.

hom*oplasmy and bottleneck

There are 5–10 copies of mtDNAs in one mitochondrion, and 1000–5000 copies in one cell in the case of the somatic cell.²⁵ The spermatozoon has approximately 50–75 mitochondria, and each mitochondrion contains, on average, one copy of mtDNA.¹ In contrast, the oocyte contains approximately 100000–400000 mitochondria, and each mitochondrion contains, on average, one copy of mtDNA.²⁶, ²⁷

In a physiological condition, all the mtDNA molecules are identical in a cell. This state is called ‘hom*oplasmy’. hom*oplasmy is thought to be important for the maintenance of the normal mitochondrial function through the coordinate expression of the mitochondrial and nuclear genes. Under certain conditions, two or more types of mtDNA molecules can be observed in a cell. This state is called ‘heteroplasmy’.

The hom*oplasmy is maintained by the ‘bottleneck’ mechanism in the oogenesis, by the mechanism for elimination of the abnormal mtDNA, and by degradation of the paternal mtDNA in the fertilized egg (maternal inheritance of the mtDNA). In the early developmental stage of the embryo, the mtDNA is not amplified. The mtDNAs are divided into the daughter cells upon division of the egg, resulting in a primordial germ cell that contains approximately 10–100 copies of the mtDNA.²⁶ When division and migration of the primordial cells occur, the number of the mitochondria increases. Consequently, the oogonium and primary oocyte contains 200 and 6000 copies of mtDNA, respectively.²³ As the mtDNAs replicate from one or a very small number of the template mtDNA in the process, hom*oplasmy is established in the oocyte. These mechanisms are called the ‘bottleneck’.⁷, ²⁸ In addition, although it has not been proven, the oocytes containing the abnormal mtDNA might bring about the apoptosis, and atresia occurs in the follicles containing the cells.²⁹ By this mechanism, the oocytes with the abnormal mtDNA are eliminated. The bottleneck mechanism and the mechanism for the elimination of the abnormal mtDNA act coordinately to generate the state of hom*oplasmy with the normal mtDNA in the mature oocytes. Also, as mentioned below, the paternal mtDNAs in the midpiece of the spermatozoon are digested in the fertilized egg. The state of hom*oplasmy with the normal mtDNA in the mature oocytes is maintained in a fertilized egg and early embryo by these mechanisms.

Mutations of the mitochondrial DNA

While the eukaryotic cells acquired the very effective energy production machine after obtaining the mitochondria, the reactive oxygen species (ROS) that are very harmful to the cells are generated in the mitochondria as by‐products of OXPHOS. As the mtDNAs exist near the respiratory chain complexes, the mtDNAs can be easily attacked by the ROS. Moreover, mtDNAs are not coated by the histones that defend the DNA from physical or chemical damage, and the mitochondria contain limited DNA repair mechanisms compared with that of the nucleus. Therefore, the rate of mtDNA mutation is much higher (40–100‐fold higher in some genes) than that of the nuclear DNA³⁰ because the ROS are isolated within the mitochondria in normal conditions, and the nuclear DNA is prevented from receiving an attack by the ROS.

Elimination of the abnormal mtDNA during cell division is considered to be one of the mechanisms for maintaining hom*oplasmy. However, the abnormal mtDNAs are accumulated with aging especially in the highly energy‐demanding tissues, such as the central nervous system, and skeletal and cardiac muscles. The function of the mitochondria in the tissues is impaired when the ratio of the abnormal mtDNAs increase above the threshold level (this level is variable according to the type of abnormality).

Various point mutations, duplications and deletions of the mtDNA have been reported, especially in the D‐loop region.³¹ The accumulation of the abnormal mtDNAs, inherited from the mother, causes a degenerative disorder, especially in the tissues with high energy demands. In addition, a part of the deletion mutants of the mtDNA has been demonstrated to be caused by the abnormality of the nuclear gene essential for the maintenance of the mtDNA or mitochondria function, and this type of abnormality is inherited according to the Mendelian rule. The disorder, caused by the abnormality of the mtDNA itself and the nuclear gene for the mitochondria, is called ‘mitochondrial disease’.⁴, ⁵, ³² The mechanism by which the abnormal mtDNAs are transmitted from mother to child, in spite of the presence of the bottleneck mechanism, has not been clarified so far. The various deletion mutations such as the deletion of the 4977bp (‘common deletion’) are also observed with aging. In the case of the ‘common deletion’, the ratio of the mutant mtDNA is 2–3%. The effect of the 2–3% of the mutant mtDNA on the cell function has not been elucidated. It should be noted that a recent report demonstrated that a novel point mutation in the D‐loop region possesses a close relation to aging.³³

MITOCHONDRIA IN THE SPERMATOZOON

Morphological feature of the sperm mitochondria

IN THE HUMAN sperm, approximately 50–75 pieces of the mitochondria helically wrapped the outer dense fibers of the tail, and they are arranged end to end in the midpiece region (Fig.3).¹ This structure of the sperm mitochondria is called the ‘mitochondrial sheath’. Although the ultrastructure and function of the sperm mitochondria are essentially similar to those of the somatic cells, the sperm mitochondria demonstrate a crescent shape. This characteristic structure, called the ‘mitochondria capsule’, is formed by disulfide bonds between the cysteine‐ and proline‐rich proteins. The sperm mitochondria become mechanically stable and resistant to the hypo‐osmotic environment because of the mitochondria capsule. Recently, it has been reported that one of the proteins making up the mitochondria capsule is the phospholipid hydroperoxide glutathione peroxidase (PHGPx).³⁴ According to this report, during spermatogenesis, the mitochondrial PHGPx play a role in its original anti‐oxidative function. However, in the mature sperm, by the formation of the intermolecular disulfide bonds among the mitochondrial PHGPx, the protein loses its enzymatic activity and is used for a structural protein for the mitochondrial sheath. More recently, it has been reported that certain cases of male infertility are reported to be involved in the lower expression level of the sperm mitochondrial PHGPx in the human.³⁵ Further studies on the sperm PHGPx are necessary to reveal the entire function of this protein.

Abnormal sperm mitochondrial DNA and sperm function

In the human spermatozoa, one copy of mtDNA is present in one mitochondrion on average.¹ The sperm mtDNA sequence is identical to that of the somatic cells, but the DNA repairing activity in the sperm is less than that in the somatic cells, or is absent altogether.³⁶ Therefore, although the mature sperm is generated from the mitotic cell (spermatogonia) and the lifespan is much shorter than that of somatic cells, the mutations of the mtDNA are demonstrated to rapidly accumulate in the sperm. This fact suggests the necessity of the maternal inheritance of the mtDNA (the elimination of the sperm mtDNA in the fertilized egg). Conversely, because of the non‐transmission of the sperm mtDNA to a descendant, the sperm mitochondria do not need to repair the abnormality of the mtDNA, nor eliminate the abnormal mtDNA. Thus, the sperm mitochondria are reported not to possess the repair mechanism of the mtDNA.³⁷ Based on this information, many researchers have studied the various mutations, duplications and deletions in the human sperm mtDNA, and investigated the relation between the abnormal mtDNA and sperm movement. However, recent reports have revealed that abnormal mtDNA is observed in 84–86% of the ‘normal’ fertile sperm, and the proportion of the abnormal mtDNA to the wild‐type mtDNA does not correlate to the movement of the sperm.³⁶

In contrast, a part of the hereditary type of abnormal mtDNA, which is the deletion mutant of the mtDNA caused by the abnormality of the nuclear gene for the maintenance of the mtDNA, and the abnormal mtDNA in mitochondrial disease, are the cause of astenozoospermia and male infertility.³⁸ However, few cases of the hereditary type of abnormal mtDNA can be found in the daily clinical cases of the oligoastenozoospermia.

The position and frequency of the point mutation, duplication or deletion of the mtDNA, and the relationship between these abnormalities and male infertility must be thoroughly investigated in future studies.

Mechanism of recognition and degradation of sperm mitochondria in fertilized eggs

Although the paternal mitochondria enter an egg on fertilization, the paternal mtDNA only constitutes a minor fraction of the mtDNA in the fertilized egg. The paternal mitochondria and mtDNA are then rapidly degraded early in the embryogenesis. Thus, the mtDNA of the paternal gamete is not transmitted to the descendant, and only the maternal mtDNA in the cytoplasm of the maternal gamete is transmitted. This mode of inheritance of the mtDNA has two biological meanings; these are: (i) maintenance of the hom*oplasmy state in the fertilized egg; and (ii) avoiding the transmission of the aberrant mtDNA in the sperm to the descendant.

One possibility for the mechanisms was suggested in a recent study where the sperm mitochondria were tagged with ubiquitin, which is a marker for protein degradation, and where the sperm mitochondria are selectively destroyed by the proteasome in the fertilized egg.³⁹

CONCLUSION

SPERM MITOCHONDRIA PLAY essential roles in fertility by supplying energy for sperm motility. However, as discussed here, many important issues are still obscure; that is, mechanisms of male infertility caused by abnormal mtDNA, including their effects on spermatogenesis and also mechanisms of specific degradation of paternal mtDNA in fertilized eggs. To understand more about the biological significance of mitochondria in the processes for the preservation of a species, further basic studies on mtDNA, as well as mitochondria, are required.

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Articles from Reproductive Medicine and Biology are provided here courtesy of John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.

As a seasoned expert in the field of reproductive medicine and biology, my extensive knowledge allows me to delve into the intricacies of the article titled "Mitochondrial DNA and its maternal transmission in fertilization and male infertility," authored by Shuji Hirata, Kazuhiko Hoshi, Tomoko Shoda, and Tadashi Mabuchi, published in Reproductive Medicine and Biology in September 2002 (DOI: 10.1046/j.1445-5781.2002.00007.x). This article explores the critical role of mitochondria, particularly mitochondrial DNA (mtDNA), in eukaryotic cells, with a specific focus on human spermatozoa and its implications for male infertility.

Overview of Key Concepts:

Mitochondria and ATP Production:
- Mitochondria are crucial organelles responsible for ATP production through the electron transport chain and oxidative phosphorylation.
- The article emphasizes the role of mitochondria in human sperm, where they provide energy for sperm motility.
Mitochondrial DNA (mtDNA):
- Mitochondria have their own genome, known as mitochondrial DNA (mtDNA), which encodes a limited number of genes.
- The article discusses the association between mutations in mtDNA and diseases, including astenozoospermia and male infertility.
Fertilization and Maternal Inheritance:
- The paternal mitochondria and mtDNA are rapidly degraded early in embryogenesis, leading to the maternal transmission of mtDNA to the descendant.
- The process of maternal inheritance of mtDNA during fertilization is a key focus of the article.
Basic Structure and Function of Mitochondria:
- Mitochondria have a double-membrane structure comprising an outer membrane and an inner membrane, creating compartments known as the matrix and intermembrane space.
- The inner membrane contains respiratory chain complexes essential for oxidative phosphorylation, contributing to ATP generation.
Mitochondrial DNA Characteristics:
- The human mitochondrial genome is a circular DNA of 16,569 base pairs, encoding proteins, ribosomal RNAs, and transfer RNAs.
- The article provides a detailed overview of the respiratory chain complexes encoded by mitochondrial genes.
Replication Mechanism of mtDNA:
- The article discusses two mechanisms of mtDNA replication: strand-asynchronous, asymmetric replication, and coupled leading- and lagging-strand, unidirectional replication.
hom*oplasmy and Bottleneck:
- The concept of hom*oplasmy, where all mtDNA molecules are identical, is maintained through a bottleneck mechanism during oogenesis, ensuring normal mitochondrial function.
Mutations of mtDNA:
- The higher mutation rate of mtDNA compared to nuclear DNA is attributed to the generation of reactive oxygen species (ROS) in mitochondria.
- Various point mutations, duplications, and deletions in mtDNA are associated with degenerative disorders.
Mitochondria in Spermatozoa:
- Human spermatozoa have a unique structure with approximately 50–75 mitochondria forming a mitochondrial sheath in the midpiece of the tail.
- Abnormalities in sperm mtDNA are explored in the context of male infertility.
Recognition and Degradation in Fertilized Eggs:
- The article addresses the mechanisms by which paternal mitochondria and mtDNA are recognized and rapidly degraded in fertilized eggs, ensuring maternal inheritance.

In conclusion, this article provides a comprehensive exploration of mitochondrial function, mtDNA characteristics, and their implications for fertilization and male infertility. The wealth of information presented underscores the significance of mitochondria in reproductive processes and the potential consequences of mtDNA abnormalities in male fertility.