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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 1  |  Page : 45-54

Mitochondrial Dysfunction and Age - related Oocyte Quality


1 Center for Reproductive Medicine, the 10th People's Hospital of Tongjin University, Shanghai 200072, China
2 Center for Reproductive Medicine, the 10th People's Hospital of Tongjin University, Shanghai 200072, China; Department of Obstetrics and Gynecology, McGill University, Montreal, Canada

Date of Web Publication17-Jul-2017

Correspondence Address:
Ri-Cheng Chian
Center for Reproductive Medicine, The 10th People's Hospital of Tongjin University, Shanghai, China Department of Obstetrics and Gynecology, McGill University, Montreal

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.210693

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  Abstract 

Fertility disorders have become a growing problem worldwide. It is well known that female fertility decreases with age, previous studies suggested that the age-related decline in female fertility potential was largely due to decrease in oocyte quality and mitochondrial dysfunction. Mitochondria play a crucial role during the process of oocyte maturation. Mitochondrial genetic, numerical and structural defects occur in oocyte aging process, mitochondrial abnormalities are believed to contribute to age-related infertility. Improvement of the mitochondrial function can lead to better fertility outcomes, and application of mitochondria replacement strategy or mitochondrial transfer to age-related infertility will be possible in the future. This review paper, we are trying to discuss current understanding about age-related changes in oocyte quality and mitochondrial dysfunction.

Keywords: Mitochondrial Dysfunction; Oocyte Quality; Therapeutic Strategies


How to cite this article:
Li H, Chian RC. Mitochondrial Dysfunction and Age - related Oocyte Quality. Reprod Dev Med 2017;1:45-54

How to cite this URL:
Li H, Chian RC. Mitochondrial Dysfunction and Age - related Oocyte Quality. Reprod Dev Med [serial online] 2017 [cited 2020 Aug 13];1:45-54. Available from: http://www.repdevmed.org/text.asp?2017/1/1/45/210693




  Introduction Top


Fertility disorders have become a growing problem worldwide.[1],[2] The success rate of assisted reproductive technology is lower in older women, which causes significant reproductive health problems for humans. It is well known that female fertility decreases with age, and previous studies have suggested that the age-related decline in female fertility potential was largely due to a decrease in oocyte quality and mitochondrial dysfunction.[3]

Oocyte aging related to postovulatory aging and advanced maternal aging are two different physiological processes. Here, we will focus on advanced maternal age-related changes in oocyte quality. The maternal aging process may affect oocyte competence through its impact on cytoplasmic quality, particularly affecting the mitochondria. The age-related changes in oocytes are complex, and there are several other potential mechanisms including metabolic disorders, genomic instability,[4] telomere shortening [5] and changes in several cell signaling systems.

Mitochondria are important organelles with critical functions in adenosine triphosphate (ATP) production, maintenance of calcium homeostasis,[6] fatty acid oxidation, cell signaling, and apoptosis.[7] Mitochondria are essential for oocyte maturation, fertilization, and embryonic development.[8] Competent mitochondrial activity is related to mitochondrial structural changes, mutation loads, mitochondrial DNA (mtDNA) copy number, and motility of mitochondria, which allows them to move to appropriate sites to provide sufficient levels of energy for local activities.[9],[10],[11] Dysfunctional mitochondria significantly decrease ATP synthesis in oocytes, with adverse effects on spindle formation, chromosomal segregation, and fertilization, resulting in decreased oocyte quality and aneuploidy.[9],[12],[13] Furthermore, because mitochondria are maternally inherited in mammalian embryos, mitochondrial mutations or deletions can be transmitted to the next generation.[14] Several lines of evidence suggest that the life span of offspring is affected by maternal age. Inheritance of mtDNA from the mother, as well as epigenetic factors,[15],[16] may play significant roles in this effect. In this review, we will summarize data about age-related changes in oocyte quality and mitochondrial function.


  Age-Related Changes in Oocyte Top


Oxidative stress and antioxidative defense

Oocytes mostly rely on energy produced by mitochondria via oxidative phosphorylation.[17] Mitochondria play an important role in oxidative stress associated with aging and infertility.[14] Reactive oxygen species (ROS) are generated during the process of ATP production. mtDNA is located near the ROS-generating electron transport chain but lacks the protection that would be provided by introns or histone proteins. After the long phase of quiescence of the oocyte during oogenesis, ROS-induced damage is expected to occur in mtDNA with a higher frequency than it does in nuclear DNA, and mutations may accumulate at a higher rate because of the low mtDNA repair capacity of mitochondria. During cell aging, exposure of the mitochondrial genome to ROS increases, and ROS can cause oxidative damage to mtDNA if they are not detoxified.[12]

Although mitochondria participate in ROS production, they also contribute to ROS detoxification that minimizes the potentially harmful effects. In vivo, granulosa cells express antioxidative enzymes such as superoxide dismutase and glutathione peroxidase, which could protect oocytes from oxidative damage. A comparison of the transcriptomes of young and aged oocytes suggests that gene expression involved in antioxidative protection is downregulated in oocytes and cumulus cells with increased maternal age.[18],[19],[20] In summary, it has been suggested that the effects of chronic, low-level ROS generation by mitochondria during the long lifetime period are associated with the accumulation of mtDNA deletions in the mature human oocyte.[21] During aging processes, a decline in antioxidant defense and increased oxidation of mtDNA may cause mitochondrial dysfunction that affects fertilization and development competence of the oocytes.[23],[24]

Energy supply and demand imbalances

During the process of fertilization, cortical granules exocytosis, chromosome segregation, and first and second polar body extrusion all require energy, which is mainly provided by ATP produced by oxidative phosphorylation in the mitochondria. It has been demonstrated that normal fertilization and early embryonic development potential are related to the ATP levels in human oocytes.[24]

Maternal aging is associated with significantly lower mtDNA copy numbers and increased frequency of mtDNA mutations.[25] It is possible that the age-related decrease in mitochondrial function impairs the process of ATP synthesis and decreases the energy content of the cell.[22],[26] Mitochondrial abnormalities and decreased energy availability compromise oocyte maturation, fertilization, and preimplantation embryogenesis, leading to arrested cell division and abnormal fragmentation of the embryo.[17],[27] ATP deficits result in an increased incidence of aneuploidy through affecting the nuclear spindle activity and chromosomal segregation.[3],[28] The rate of aneuploidy in human oocytes increases with maternal age, from 20% in 35-year-old women to about 60% in women aged 43 years and older.[29] Previous studies have suggested that the cellular concentration of mitochondrial proteins and ATP may have wide-ranging effects on nuclear gene expression, including epigenetic modification, transcription, and protein synthesis.[30] Thus, energy supply and demand imbalances in oocytes could affect cell activities through influencing the expression of nuclear genes.

Apoptosis and defects in calcium regulation

Apoptosis is associated with physiologic or programmed cell death. Mature oocytes will degenerate if they are not fertilized. Mammalian oocytes express several anti- and pro-apoptotic members of the Bcl-2 family, and the balance between these factors is critical for oocyte survival.[17],[31] Mitochondria are involved in this process and play an important role in apoptosis of oocytes and early embryos.[32],[33] In fact, a group of anti-apoptotic genes are shown to be downregulated in aged mouse oocytes both in vivo and in vitro.[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34] Mitochondria also integrate the mitochondrial permeability transition pores that initiate cell death when the mitochondrial energy function declines.

Calcium oscillations are known to be an essential step of oocyte activation leading to the completion of meiosis.[35] Mitochondria play a role in maintaining calcium homeostasis by serving as calcium stores and are involved in the regulation of sperm-triggered calcium oscillations.[36] The signal can be directly transmitted to the mitochondrial matrix, affecting the expression of respiratory chain enzymes and increasing ATP production,[37] which is in turn necessary for the maintenance of calcium oscillations.[38] Oocytes with low levels of ATP production may be unable to maintain the sperm-triggered calcium oscillations, thus inducing the apoptotic pathway.[39],[40] Calcium overload, overexpression of the pro-apoptotic Bcl-2 proteins, or opening of the mitochondrial permeability transition pores can lead to release of cytochrome c and activation of the apoptotic pathway.[31],[41],[42] Previous studies have suggested that DNA fragmentation associated with apoptosis might be one of the reasons for poor oocyte quality and lower fertility in older women.[43]

Altered environment and bidirectional signaling

The oocyte maintains cytoplasm connections with the cumulus cells surround it. These connections allow for transport of nutrients to support the metabolic needs of the oocyte. Oocyte and granulosa cells depend on the ovarian microenvironment, which is altered during aging, particularly by the influence of oxidative stress.[44] The intrafollicular environment can affect centrosome-based microtubule assembly, including spindle formation, which accounts for an increased incidence of aneuploidy with age.[45] Advanced female age can also impact the cumulus cells' gene-expression profile. Previous study has shown that expression of mitochondrial function and antioxidant protection genes in cumulus cells are impacted by advanced maternal aging, a compromised follicular environment is evident with altered energy metabolism and posttranscriptional processes.[46] Granulosa cells from women over 38 years of age have been shown to contain higher levels of mtDNA deletions and damaged mitochondria than do those from younger women.[47] Consistent with these findings, granulosa cell apoptosis occurs at higher rates in older in vitro fertilization patients,[48] accompanied by altered gene and protein expression for pathways involving angiogenesis, insulin signaling,[49] lipid metabolism, and oxidative phosphorylation.[46] The cumulus cells and follicular fluid also contribute to the antioxidative defense of oocytes.[50],[51] Age-related oxidative damage in granulosa cells and interstitial ovarian tissue of aged mice [48] and diminished expression of antioxidant enzyme in granulosa cells of women over 38 years of age [47] have been reported. Age-related reductions of intrafollicular glutathione peroxidase, reductase, and synthetase, as well as peroxiredoxins 1 and 2, occur in natural menstrual cycles.[52]

Recent studies have shown a significant link between the mtDNA content of human cumulus granulosa cells surrounding an oocyte and the embryo quality, with significantly higher mtDNA copy numbers being associated with high-quality embryos.[53],[54] Cumulus cells also play an important role in maintaining an mtDNA pool sufficiently large to ensure oocyte competence through the expression of factors involved in mtDNA replication and maintenance. Altered metabolic pathways in cumulus cells can reflect impaired mitochondrial biogenesis during folliculogenesis in ovarian aging.[1],[55]

It has been proposed that analysis of gene expression of key genes within cumulus cells,[56] for example, genes involved in metabolism, steroidogenesis, and signaling, may be a useful, noninvasive tool for assessing oocyte quality, which could shed light on embryo quality and probable pregnancy and birth outcomes.[57],[58] Ovarian aging also seriously affects the dynamic nature of mitochondrial biogenesis in the surrounding granulosa cells, which may provide alternative biomarkers of oocyte quality.[54]


  Mitochondrial Dysfunction during Aging Top


Mitochondrial numbers and mitochondrial DNA copy numbers

Different tissues have different numbers of mitochondria and mtDNA copies, depending on their metabolic activity.[14] Oocytes have the largest number of mitochondria and mtDNA copies of any somatic cells, and each mitochondrion in the oocyte is thought to contain only one or two mtDNA copies.[59],[60] Oocytes appear to have many more mitochondria than are required for normal maturation. Some believe this is because oocytes need a large number of mitochondria to prepare for the increased energy demands of successful fertilization and early embryonic development. Mitochondrial synthesis is closed at the metaphase II stage and not reactivated in the embryo until blastocyst implantation.[36] The total number of mitochondria or mtDNA copies in the developing embryo does not change from fertilization until the blastocyst stage.[61] Mitochondrion numbers within each blastomere decrease due to distribution.[62] Therefore, the oocyte mitochondrial pool is the major energy source of the preimplantation embryo and is vital to maintaining embryo development until mtDNA replication.[63] Furthermore, research in cattle models has found that under certain conditions, the embryo could prematurely initiate mtDNA replication.[64] Another study found that downregulation of mtDNA replication at the end of pig oocyte maturation may be essential for successful preimplantation development.[65] Mammalian mtDNA copy numbers vary among animal species. Human oocytes have been shown to vary from 138,000 to 697,176 mtDNA copies.[23],[66],[67],[68],[69],[70],[71],[72] Previous analyses of mitochondria and mtDNA copy numbers per mature human oocyte have suggested a large variability,[71] even within oocytes from the same individual.[66],[73] Oocytes with fertilization failure had 152,000 mtDNA molecules,[69] while in ovarian insufficiency, the count of mtDNA was 100,000.[72] Some studies have shown that the impaired oocyte quality associated with insufficient mtDNA content could cause premature mitochondrial biogenesis, leading to the failure of development.[71] Other studies suggest that the development is not compromised unless a critical threshold is reached.[64] With the reduced number of mitochondria, the negative effects of poor mitochondrial quality and high mutational load become more evident.[12] In mice, it has been shown that oocytes with only 4000 mtDNA copies can be fertilized but fail to develop after implantation, and that at least 50,000 copies of mtDNA are needed for a mature oocyte to be able to resume development after implantation.[74] Whether the required mtDNA levels are the same in humans is unclear, though a relationship between human oocyte mtDNA copies and oocyte quality has been observed.[70] The mtDNA copy number has also been shown to be lower in unfertilized oocytes than it is in fertilized oocytes.[69]

Previous studies have demonstrated that maternal age-related processes affect mtDNA copy numbers in human oocytes. Older human oocytes contain fewer mtDNA copies than do younger ones.[68],[70] However, this finding has not been confirmed by other researchers.[66] Among older women, the mtDNA content in early-cleavage stage embryos was also found to be lower than that of younger women, but at the blastocyst stage, the opposite was observed, with an increase of the mtDNA content of blastocysts from older patients.[75] Thus, mitochondrial proliferation may be a compensatory mechanism for mitochondrial insufficiency and a sign of developmental abnormality.[76],[77]

Mitochondrial DNA damage

Mitochondria are semiautonomous organelles that contain their own genomes. The mitochondrial genome consists of a double-stranded circular DNA molecule 16.6 kb long, containing 37 genes encoding for 13 proteins that are part of the respiratory chain complexes,[14] 2 rRNAs used in translation of mitochondrial subunits, and 22 tRNAs used in mitochondrial protein synthesis.[8],[14]

Accumulation of mtDNA damage is attributed to the continuous exposure to ROS generated through ATP production by the mitochondria.[78] Mitochondrial dysfunction caused by accumulated damage is implicated in the aging process. Increased mtDNA mutations and deletions, as well as respiratory chain deficiency, are apparent in many tissue types following aging.

Because oocytes can contain a large number of mitochondria, a high proportion of mutations and deletions can be tolerated before deficiency in oocyte cellular function is apparent. Previous studies have suggested that mitochondrial dysfunction is indicated when overall mitochondrial function drops below a threshold.[79] Mutations and deletions in the mtDNA of oocytes have been reported to increase with advanced female age, including the 4977-bp deletion and some point mutations.[80] Increased mtDNA mutations would cause further accumulation of ROS and increased mtDNA mutations. The mtDNA 4977-bp deletion is common in unfertilized human oocytes [68] and oocytes from older patients.[26],[81] Because mtDNA contains genes encoding proteins of the respiratory chain, a significant loss of mtDNA will ultimately result in dysfunctional oxidative phosphorylation [17] and will negatively impact some cellular activities, such as chromosomal segregation and fertilization and development of the preimplantation embryo. Recently, a study showed that ovarian aging in a bovine model increased the number of oocytes exhibiting mtDNA deletions, but there was no evident relationship between advanced female age and the presence of mtDNA heteroplasmies.[82] While other studies found no evident increase in the number of mtDNA mutations with age,[21] this observation supports the hypothesis that there is an age-related accumulation of mtDNA rearrangements in human oocytes.[83],[84] It has been shown that the incidences of mtDNA rearrangements are inversely related to oocyte development,[83] suggesting a possible selection process such that immature oocytes with mitochondrial deletion do not develop further.[68]

In addition to aging as a cause of mtDNA damage, clonal expansion of preexisting mtDNA mutations can in turn lead to aging due to mitochondrial dysfunction.[85] Finally, inherited and acquired mtDNA damage act together to bring on the phenotype of aging, including infertility.[86] Oocyte mitochondria with mutations can pass these mutations to the offspring.[9],[87] Recently, a positive correlation has been reported between the number of mtDNA heteroplasmic mutations in the blood cells of a child and the age of the child's mother at the time of fertilization.[88]

Morphology and membrane potential changes

Mitochondria have structural differences correlated with the different metabolic demands. Mature oocytes use glycolysis and the pentose phosphate pathway, and their mitochondria are immature and small with round or oval shapes, and they have only few cristae and an electron-dense matrix.[9],[17] After fertilization, with embryo-progressive development, mitochondria undergo structural maturation and gain their elongated shape with transverse cristae and a less electron-dense matrix.[89],[90] Mitochondrial swelling and cristae damage are common structural features of oocytes from older women.[27] Morphometric analyses of human oocytes show an increase in mitochondrial density, size, and volume fraction with increasing age. In these instances, swelling may be caused by an imbalance of volume homeostasis.[91] The increase in mitochondrial size could also be a compensatory expansion to correct for decreased energy production or impaired mitochondrial clearance resulting from the aging process.[92]

During oocyte maturation, mitochondrial membrane potential (Δψm) is highly important for oocyte quality.[93] The differences of Δψm at the inner mitochondrial membrane can reflect functional diversity of mitochondrial activities in oocytes.[94],[95] More highly polarized mitochondria potentially contain a higher bioenergetic capacity. Stage-related increased Δψm can be coincident with increased ATP levels and can be involved in the local regulation of oocyte activities such as ATP generation, signaling,[96],[97] and maintaining calcium homeostasis in the cytoplasm.[98] Some studies have shown that the Δψm is decreased in the mitochondria of oocytes and embryos with advanced maternal aging in humans.[95],[99] Δψm has been investigated as a developmentally relevant factor for fertilization and early embryonic developmental potential.[98],[100],[101]

Distribution during oocyte maturation

Mitochondria are highly dynamic organelles that continuously move during normal oocyte maturation process. Mitochondria are stage specifically distributed to different sites in cytoplasm, in response to local energy needs.[102] For example, mitochondria become localized to the nuclear periphery during germinal vesicle (GV) breakdown and then disperse to the periphery again.[103],[104] During the second meiotic division, mitochondria are mainly present around the spindle and then disperse to the cytoplasm.[20] These distribution patterns support the local generation of energy for spindle formation and oocyte activation after fertilization. The dispersal of mitochondria after germinal vesicle breakdown and meiosis I and II appears to be correlated with a brief reduction in ATP generation.[102],[103] The regulation of mitochondrial dynamics is important for oocyte maturation. By locally increasing mitochondrial density, demand for ATP may be met in the specific location without involving all the mitochondria in the cytoplasm, ensuring that mitochondria are exposed to lower levels of oxidative stress. Patterns of mitochondrial distribution in the mature oocyte seem to differ among species.[37],[103],[105],[106] Animal studies have shown that abnormal mitochondrial distribution decreases the developmental competence of mouse oocytes. It is important to clarify whether mitochondrial donation might be sufficient to overcome local requirements for high energy demand.[107]

Mitochondria go through frequent cycles of fusion and fission in order to maintain mitochondrial function in response to variations of cellular energy demand. Mitochondrial fission generates new mitochondria necessary for cellular growth and facilitates the degradation and elimination of damaged mitochondria by mitophagy.[108] Mitochondrial fusion assures close complementation between organelles to meet dynamic energy needs.[109] Udagawa et al.[110] established oocyte-specific Drp1-deficient mice and found that mitochondrial fission maintains the competency of oocytes via multi-organelle rearrangement in an age-dependent manner.


  Therapeutic Strategies to Overcome Mitochondrial Dysfunction Top


Mitochondrial nutrients

One potential approach to overcome energy deficits in oocytes is to use mitochondrial nutrients to enhance respiratory chain function and mitochondrial ATP generation.[111],[112] Mitochondrial nutrients may be able to reduce the risk of cytoplasmic fragmentation and chromosomal aneuploidies related to oocyte aging. Identification of orally active compounds that boost the energetic capacity of oocytes before ovulation or retrieval for in vitro fertilization may therefore provide a novel strategy to maximize the chances of obtaining viable eggs from women at advanced reproductive ages.[111] These compounds may include coenzyme Q10 (CoQ10), α-lipoic acid (ALA), resveratrol, sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), and metformin. Dietary supplementation with CoQ10 can improve mitochondrial function in oocytes and developing embryos and may decrease the aneuploidy rate in human oocytes.[113] CoQ10 is a key enzyme in energy production and a major cellular antioxidant [114] that aids in the transport of electrons in the mitochondrial respiratory chain and is essential for the stability of complex III.[115] ALA is a coenzyme involved in mitochondrial metabolism. The reduced form of ALA is a powerful mitochondrial antioxidant formed by nicotinamide adenine dinucleotide-dependent mitochondrial dihydrolipoamide dehydrogenase.[116] The SIRT1-AMPK network acts to increase both the number and activity of mitochondria,[117] so the mimetics that stimulate SIRT1 or AMPK activity can function as mitochondrial nutrients. These mimetics include resveratrol,[118] SRT1720,[119] and metformin.[120],[121] In addition, SIRT3, a member of the SIRTuin family, has emerged as a mitochondrial fidelity protein that directs energy generation and regulates ROS-scavenging proteins.[122] Loss of SIRTuin-3 function in mouse eggs increases mitochondrial ROS production, leading to impaired preimplantation embryonic development after fertilization.[123] Research has shown that dysfunction of the SIRTuin-3 gene contributes to the failure of mitochondrial biogenesis, resulting in developmental inefficiency of in vitro maturation-metaphase II (MII) oocytes.[124] Although the use of mitochondrial nutrients to improve fertility is appealing, well-designed clinical studies are required to test the clinical efficacy and potential benefits of this approach.[125]

Mitochondrial transfers

Cytoplasmic transfer usually refers to the supplementation of an oocyte with donor cytoplasm containing healthy, active mitochondria.[126],[127] The development competence of oocytes and embryos can be enhanced by transferring healthy cytoplasm or mitochondria from young oocytes into the aged oocytes.[128],[129] It is suggested that mitochondrial transfer could be a therapeutic strategy for infertility patients with age-related impairment of oocyte quality or recurrent in vitro fertilization failure.[130] However, the benefits and safety of this technology have not been fully proven, and cytoplasmic transfer cannot prevent the transmission of a mitochondrial disorder.

One problem that must be taken into account is the potential risk of mitochondrial heteroplasmy.[101] It has been reported that mitochondrial heteroplasmy causes negative effects in offspring.[131],[132] Studies in mice have shown that mitochondrial heteroplasmy can negatively impact cognitive and metabolic function.[133],[134] There is a reciprocal interaction between the nuclear and mitochondrial genomes.[13],[29] Mitochondria influence the stability of the nuclear genome and nuclear gene expression,[29],[135] and in turn, mitochondrial replication is controlled by several nuclear DNA-encoded transcription factors, as well as mtDNA polymerase.[136] Mitochondrial function varies widely among cell and tissue types, and proteins encoded by nuclear DNA are imported into the mitochondria to control their function in a tissue-specific manner.[137],[138] Therefore, the optimal source for mitochondria transfer to overcome oocyte aging would be the patient's own cells, and the cell type should be closely related to oocytes in origin in order to maintain homoplasmy and optimal communication between nuclear and mitochondrial genomes. Although the use of autologous mitochondria from a patient's own somatic or granulosa cells would avoid mitochondrial heteroplasmy, somatic mitochondria are expected to contain age-related mtDNA damage,[139] so transmission of these mutations and deletions to offspring would be a potential risk.

Previous studies have suggested that adult mammalian ovaries are not endowed with a finite number of oocytes but, instead, possess stem cells that contribute to the renewal of oocyte numbers.[26],[140],[141] While such ovarian germ-line stem cells are characterized in nonmammalian model organisms, findings that support the existence of adult ovarian germ-line stem cells in mammals have been controversial.[142] The ability to isolate and promote the growth and development of such ovarian germ-line stem cells would provide a way to treat infertility in women.[143] These oocyte precursor cells might serve as mitochondria donors because they can differentiate to the oocyte lineage and have not been damaged by ROS for a long period of time.[144] This kind of cell may provide high-quality homoplasmic mtDNA without mutations or deletions.[145]

Mitochondria replacement therapy

The oocytes and blastocysts in women of advanced reproductive age contain numerous mitochondrial mutations, deletions, and nucleotide variations, some of which may be considered unsafe for transmission to offspring.[146] Mitochondrial mutations cause a number of diseases, and mitochondria replacement or nuclear transfer may be a way to overcome mitochondrial dysfunctions and avoid the transmission of mtDNA damage to offspring.[29],[147] Nuclear transfer is a process in which the nuclear DNA is moved from an oocyte or zygote with abnormal mtDNA and transferred into a donor oocyte containing healthy mitochondria.[139],[148] Alternative approaches include pronuclear transfer, spindle transfer, and polar body transfer. Now, patient selection is restricted to specific patients carrying homoplasmic or high heteroplasmic mtDNA mutations, whose offspring would otherwise have severe mtDNA disease.[126]

In spindle transfer, either GV or MII spindle–chromosome complexes are removed from the patient's unfertilized oocyte and inserted into an enucleated oocyte containing healthy mitochondria.[148],[149] MII transfer is less invasive, and because the distribution of mitochondria in oocytes is uniform,[18] the chromosomes can be isolated with high efficiency and less mtDNA is transferred.[147],[150] However, high levels of abnormal fertilization and premature oocyte activation during spindle transfer [151] suggest that human oocytes are sensitive to manipulation. Spindle transfer may introduce an abnormal centrosome number, resulting in multipolar spindles and aneuploidy.[91] A new study has suggested that nuclear genome transfer would be more effective than would the transfer of intact spindle–chromosome complexes in preventing the transmission of mtDNA mutations.[148] Pronuclear transfer uses a similar basic procedure as does spindle transfer. The male and female pronuclei are visualized shortly after fertilization.[152] Recent literature describes the development of an alternative approach involving transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division, thus reducing carryover to the lowest possible levels.[153] A polar body contains only a few mitochondria, yet contains the same amount of nuclear DNA as does an oocyte.[18] Recent work has demonstrated that polar body transfer also has great potential to prevent the transmission of inherited mtDNA diseases.[154],[155]

The techniques mentioned above have the potential to reduce the risk of mtDNA diseases, but the cotransfer of a small amount of the patient's mitochondria into the donor oocyte cannot be avoided. Some studies suggested that the transfer of less than 2% of the heteroplasmic mitochondria would not cause health problems.[145] However, researchers are concerned that one mitochondrion could copy its DNA faster than the others do when large DNA-sequence differences exist between two populations of mitochondria.[156] Another possible problem is the disruption of specific mitochondrial and nuclear genome interactions. Interactions between the mitochondria and the nucleus and phenotypic penetrance of mtDNA heteroplasmy need to be further investigated.[157] Interestingly, Zhang et al.[158] reported the first live birth after spindle–chromosomal complex transfer, revealing that studying the role of mitochondria in oocyte maturation and aging will help welcome a new page in reproductive technology.


  Conclusion Top


Age-related changes in oocytes are complex, including increased oxidative stress, impaired mitochondrial function, genomic instability, and changes in several cell signaling systems. Mitochondria play a crucial role during the process of oocyte maturation. Mitochondrial dysfunction affects normal oocyte development, and a decreased number of mitochondria contribute to oocyte aging. Mitochondrial abnormalities are believed to contribute to age-related infertility. Mitochondrial genetic and structural defects, as well as a decrease in the number of mitochondria, can occur in the oocyte aging process. The molecular factors and concrete mechanisms responsible for oocyte mitochondrial abnormalities remain to be elucidated. Improvement of mitochondrial function could lead to better fertility outcomes, while the application of mitochondrial replacement or transfer strategies to age-related infertility may be possible in the future. The effects of mitochondrial heteroplasmy, and the relationship between the mitochondrial and nuclear genome, still need to be further investigated.

Financial support and sponsorship

This work was supported by funding (to Chian RC) from the Ministry of Science and Technology of China (grants 2017YFC1001601).

Conflicts of interest

There are no conflicts of interest.



 
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