1J Contemp Med Sci | Vol. 6, No. 1, January–February 2020: 1–7 Review ISSN 2413-0516 Introduction Premature ovarian failure (POF), also known as premature ovarian insufficiency, is used to describe women under 40 years old with amenorrhea, hypergonadotropic hypogonad- ism, and infertility as a result of cessation of ovarian function.1, 2 It has been estimated that POF affects 1 in 100 women under 40 years, 1 in 1000 women under 30 years, and 1 in 10,000 of women under 20 years.1,3 There is a higher risk of early menopause in women with poor response to ovarian stimu- lation undergoing assisted reproductive technology (ART). The results of a 10-year follow-up of women younger than 40 years of age with poor ovarian response in IVF cycles indi- cated that 11% of them developed early menopause and 3% of them developed POF.4 In the large majority of cases, ovarian failure is initiated after puberty.5 Secondary amenorrhea associated with prema- ture depletion of ovarian follicles or arrest of folliculogenesis occurs in women with post-pubertal POF. The clinical char- acteristics of patients with POF include flushes, heat intoler- ance, irritability, night sweats, sleep disturbance, palpitations, fatigue, anxiety, depression, hair coarseness, infertility, vagi- nal dryness, and decreased libido.3 Furthermore, POF and a long-term delay in estrogen replacement therapy may result in early-onset osteoporosis. Deficiency of sex hormones is con- sidered a crucial risk factor for metabolic, cardiovascular, or neurological diseases.3 Hormonally, POF is characterized by low levels of estrogens and inhibins and high levels of LH and FSH.3 Estrogen/progestin preparations are effective to treat hor- monal deficiency in patients with POF. It has been reported that almost 20% of women who consult for infertility have signs of premature ovarian ageing.6 Although, restoration of fertility cannot presently be done if the diagnosis of POF is made after the full depletion of the follicular pool, early diag- nosis by genetic testing may provide the opportunity for fertil- ity preservation. At present, ovum donation is the only option available for treatment of infertility in women with absence of ovarian reserve.3 Although in majority of cases, the underlying cause of POF is not identified, the known causes include: genetic aberrations; autoimmune ovarian damage; iatrogenic com- plications following surgery, radiation therapy, and chemo- therapy; and environmental factors such as viral infections and toxins.7 Furthermore, several studies have reported an association between mitochondrial diseases and POF in both animals and humans.8–11 Oocyte mitochondrial depletion has been observed in patients with poor recovery rates of mature oocytes after ovarian hyperstimulation and in women with ovarian insufficiency.12,13 Due to the maternal inheritance of POF along with the dependence of folliculogenesis upon the mitochondrial biogenesis and bioenergetics, it has been suggested that a generalized mitochondrial defect is likely involved in POF.14 The aim of this review was to illustrate the role of mitochondria in POF. A fuller understanding of the mitochondrial role in POF could contribute to the better man- agement of women with POF in the future. Mitochondria and Ovarian Function Mitochondria are the site of cellular respiration/oxidative phosphorylation that produce the energy needed for all aspects of cellular function.15 The oxidative phosphoryla- tion system of mitochondria consists of five multi-enzymatic complexes: complexes I–IV of the electron transport chain and complex V (Adenosine triphosphate (ATP) synthase).6 The role of mitochondria in premature ovarian failure: A review Kajal Khodamoradia,b, Zahra Khosravizadehb, Zahra Rashidic, Ali Talebid,e, Gholamreza Hassanzadehb aDepartment of Urology, University of Miami, Miller School of Medicine, Miami, FL, USA. bDepartment of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. cFertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran. dSchool of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran. eClinical Research Development Unit, Bahar Hospital, Shahroud University of Medical Sciences, Shahroud, Iran. Correspondence to: Gholamreza Hassanzadeh (email: hassanzadeh@tums.ac.ir) (Submitted: 11 August 2019 – Revised version received: 04 October 2019 – Accepted: 15 October 2019 – Published online: 26 February 2020) Abstract Premature ovarian failure (POF) is used to describe women under 40 years old with amenorrhea, hypergonadotropic hypogonadism, and infertility as a result of cessation of ovarian function. It has been reported that almost 20% of women who consult for infertility have signs of premature ovarian ageing. The mitochondrial disorder is one of the critical agents in premature menopause and the occurrence of POF. Due to the maternal inheritance of POF along with the dependence of folliculogenesis upon the mitochondrial biogenesis and bioenergetics, it has been suggested that a generalized mitochondrial defect is likely involved in POF. A fuller understanding of the mitochondrial role in POF could contribute to the better management of women with POF in the future. The aim of this review was to illustrate the role of mitochondria in POF. The oocyte mitochondrial DNA (mtDNA) content in women with diminished ovarian reserve is significantly lower than women with normal ovarian reserve. It has been evidenced that mitochondrial genetic disorders and mitochondrial oxidative stress are associated with POF. According to the maternal inheritance of mtDNA, genetic testing should be performed to detect mtDNA mutations involved in POF before starting treatment strategies. If these mutations are present, it could suggest that healthy mitochondrial transfer during assisted reproductive technology should be used to prevent the transmission of POF caused by mtDNA mutation to the female offspring. Future strategies aimed at treatment of POF-related infertility should take into account the significance of the oocyte mitochondrial role in the occurrence of this disorder. Keywords premature ovarian failure, low ovarian reserve, mitochondria, infertility 2 Review The role of mitochondria in premature ovarian failure K. Khodamoradi et al. J Contemp Med Sci | Vol. 6, No. 1, January–February 2020: 1–7 It has been reported that disruption of mitochondrial oxida- tive phosphorylation in mouse oocytes leads to abnormalities in the meiotic spindle and the potential reduction of embry- onic preimplantation.16 Mitochondria functions directly affect several aspects of the reproductive process including oocyte quality, fertilization process, and embryo development.17 The mitochondrial biogenesis and bioenergetics have an import- ant role in maturation of the oocyte and embryonic devel- opment.18,19 Moreover, the results of studies showed that the oocyte mitochondrial content could affect fertilizability of the oocyte.17 Mature oocytes need large number of mitochondria and it has been shown that the mitochondrial DNA (mtDNA) content of an oocyte is strictly related to the probability of zygote development.17,20 Much of the endogenous reactive oxygen species (ROS), as a toxic by-product of oxidative phosphorylation, is gener- ated in the mitochondria. Mitochondrial dysfunctions lead to inhibition of oxidative phosphorylation and increased ROS generation that can induce apoptosis.6 Mitochondria are dis- tributed and localized in regions of the ooplasm that require higher ATP levels for an energy-consuming event, resulting in cytoplasmic and nuclear maturation of oocytes including germinal vesicle breakdown, and assembly and disassembly of microtubules for the formation of meiotic spindles.19,21,22 It seems that mitochondrial biogenesis plays a key role in determining the initial size of the ovarian follicular pool during embryonic life.23 Age-associated deterioration of mitochondria negatively influences ovarian reserve, segregation of chromo- somes, and embryo competence.24 It is well-known that female germline aging is accompanied by mitochondrial dysfunction correlated with reduced levels of oxidative phosphorylation and ATP.25 Ovarian ageing is correlated with reduced mtDNA content in oocytes.6 Older women or women with dimin- ished ovarian reserve (DOR) have significantly lower oocyte mtDNA content compared to younger women or women with normal ovarian reserve.12,26–28 According to the findings of study by Hamatani et al., the expression patterns of genes related to mitochondrial functions and oxidative stress show an age-associated alteration on mouse oocytes.29 In women with ovarian ageing, the impaired quality of the oocytes asso- ciated with insufficient mtDNA content can result in prema- ture biogenesis of mitochondria and embryonic development failure.6 Research on mice have shown that mitochondria are involved in follicle pool exhaustion with ageing by affecting the initial size of the follicular pool and the rate of follicular atresia.6 In various mammalian species, including human, the apoptotic process is involved in germ cell elimination at all oogenesis stages and in depletion of ovarian reserve.30 This process in the mammalian oocytes involves both the intrinsic mitochondrial pathway as well as the extrinsic death receptor pathway.30,31 It has been reported that mitochondria and B-cell lymphoma 2 (Bcl-2) family members are involved in ovarian apoptosis.32 Taken together, these findings strongly support the role of mitochondria in POF. Mitochondrial Genetic Disorders and Incidence of POF Several human diseases have been identified that are associated with mtDNA mutations.33 The higher mutation rate of mtDNA (approximately 25 times) compared to that of nuclear DNA is due to the proximity of mtDNA with the respiratory chain, the absence of histones, and efficient DNA repair mechanisms.34 It is known that oocytes have the largest mitochondrial genome content of an organism.17 However, the oocyte mtDNA con- tent in women with DOR is significantly lower than in women with normal ovarian reserve.6 It has been demonstrated that some cases of POF may be due to follicular atresia and elimi- nating primary oocytes with harmful mtDNA mutations.35 The human mitochondrial genome contains genes coding for 13 polypeptides, 2 rRNAs, and 22 tRNAs.36 Deficiency in the mitochondrial tRNA (mt-tRNA) genes is known to be an important factor in clinical disease.37 Ding and his colleagues assessed the association between mt-tRNA mutations and pre- mature ovarian insufficiency. Their results indicated that levels of FSH, LH, and ROS production were increased in POF com- pared to control groups. In addition to estradiol, total testoster- one levels and ATP content showed a significant reduction in the POF group. Moreover, a high incidence of mt-tRNA muta- tions was observed in these patients. The A4435G (tRNAMet), C3303T (tRNALeu), G5821A (tRNACys), T4363C (tRNAGln), and A15951G (tRNATh) mutations were recognized as patho- genic mutations related to premature ovarian insufficiency. However, their outcomes revealed that the mt-tRNA mutation itself was inadequate to cause the clinical disorders, and other risk factors may also contribute to POF development.38 In each human cell, mtDNA are replicated by DNA poly- merase gamma (pol γ), which is a holoenzyme consisting of a 140-kDa catalytic subunit (POLG) and a dimeric form of 52-kDa accessory subunit (POLG2). The POLG subunit has three main functions including DNA polymerase, 3′-5′ exo- nuclease, and 5′ dRP lyase activities.39, 40 After identifying the first disease associated with POLG gene mutation, progressive external ophthalmoplegia (PEO), association with other dis- eases and syndromes such as Alpers syndrome, ataxia-neurop- athy syndromes, Charcot-Marie-Tooth disease, and idiopathic Parkinsonism were discovered.11, 41, 42 The Y955C mutation in POLG is commonly associated with autosomal dominant PEO. Due to this mutation, many women with PEO, present indicatives of POF.9, 11 Luoma et al., in a clinical and molecular genetic study, investigated female patients with early menopause and used PEO as a POLG mutation marker. They showed that the co-segregation of pre- mature menopause with POLG mutations was significant and suggested POLG-associated PEO could become an important method in understanding the mechanisms of oxidative stress and mitochondrial dysfunction in premature menopause.9 In 2006, a study investigated three-generation pedigree with familial premature menopause associated with PEO which had apparent maternal transmission of disease.11 The proband, her mother, and her maternal grandmother all presented with PEO and subsequently developed POF at ages of 28, 35, and 32 years, respectively. The researcher found that PEO disease can be distinguished via a dominant Y955C mutation in the POLG gene and concluded that the variation of the POLG mutation can affect the age of women’s menopause.11 However, Tong et al. screened the genomic DNA of patients with POF for the 5 POLG mutations and concluded that these POLG mutations cannot be prevalent genetic etiologies for POF.43 In a small size study on the etiology of POF in young girls, a pediatric endo- crinologist found that these patients had different etiologies compared to those cases seen in adults which included con- genital disorder of glycosylation syndrome and mitochondrial 3 Review The role of mitochondria in premature ovarian failureK. Khodamoradi et al. J Contemp Med Sci | Vol. 6, No. 1, January–February 2020: 1–7 diseases. However, in their study only one POF patient was diagnosed with a mitochondrial disorder. The authors sug- gested a larger size survey should be done for further clinical recommendations among these cases.44 Chen et al. identified two different homozygous missense mutations with variants c.404G>A (p.R135Q) and c.605G>A (p.R202H) in four young females from two independent fam- ilies. These mutations were considered a novel genetic cause of POF in adolescents. This study showed that MRPS22 defi- ciency, especially in the somatic cells of the ovary, had no effect on fertility but that its mutation in germ cells results in the absence of germ cells and infertility in a Drosophila model. These findings collectively identify that MRPS22 is required for reproduction and ovarian development and may contrib- ute to ovarian dysfunction.45 Cytochrome c oxidase (COX) is one of the main enzymes in the electron transport chain of mitochondria. A mutation in the gene encoding mitochondrial COX 1 (MT-CO1) reduces COX activity and ATP production, which is correlated with dysfunction of mitochondria, increase in apoptosis,46 and fol- licular depletion in early adulthood, and is followed by POF.47 With this hypothesis, Zhen et al. screened the mitochon- drial genome of patients with POF and healthy females. They observed a significant incidence of MT-CO1 missense muta- tions in POF patients. Also, there were significant increases in FSH, LH, and E2 levels, and a significant decrease in ovar- ian volume and ATP levels compared to the control group. They proposed that MT-CO1 gene mutations may be one of the causals in POF.48 Further molecular studies are required to uncover other genetic mitochondrial disorders involved in POF. Mitochondrial genetic mutations known to be involved in POF are shown in Table 1. Mitochondrial ROS Production and Incidence of POF Mitochondria are responsible for the generation of most of a cell’s energy and their dysfunction lead to increased levels of ROS and low ATP levels.49 Accumulation of ROS leads to oxidative stress, which can activate apoptosis in the majority of germ cells in the ovary.50–52 Furthermore, pathologic accu- mulation levels of ROS in ovaries may result in tissue inflam- mation including oophoritis, necrosis, and apoptosis.53 On the other hand, increased levels of ROS induce lipid peroxidation and cause increased nuclear DNA damage,54 and mitochon- drial DNA nucleotide changes.55 Some of the female repro- ductive disorders such as endometriosis, polycystic ovary syndrome, POF, and infertility are due to oxidative stress.56,57 It has been well-known that POF is correlated with some mitochondrial disorders, and a correlation between idiopathic POF and increased oxidative stress has been described.58,59 Propionic acidemia is an autosomal recessively inherited inborn error of propionate metabolism that is caused by a deficiency of the mitochondrial enzyme propionyl-CoA Table 1. Summary of mitochondrial genetic mutations involved in the POF. Authors Species Gene Results Luoma et al. (2004) Human POLG POLG mutation is involved in the etiology of parkinsonism, PEO, and premature menopause. Most women with PEO experienced early menopause before age 35. Pagnamenta et al. (2006) Human POLG The Y955C mutation in POLG can result in mtDNA depletion. POLG mutations can cause POF and parkinsonism. Tong et al. (2010) Human POLG These POLG mutations including Y955C and R943H (c2767G>A, c2828G>A, c2857C>T, c2864A>G, and c2869G>T) are not a prevalent genetic etiology for spontaneous 46, XX POF. Brauner et al. (2015) Human NR5A1, BMP15, GDF9, and NOBOX In two cases, an NR5A1 gene mutation was detected in the pediatric population with POF. Zhen et al. (2015) Human MT-CO1 A high incidence of MT-CO1 missense variants (MT-CO1 c.790A>G, MT-CO1c.802T>C, MT- CO1 c.1165A>G, and MT-CO1 c.667G>T) was identified in POF patients that could lead to reduction of COX activity, decrease in ATP level, and mitochondrial dysfunction. MT-CO1 gene mutation may be causal in POF. Chen et al. (2018) Human MRPS22 Missense mutations in MRPS22 [variants c.404G>A (p.R135Q) and c.605G>A (p.R202H)] lead to autosomal recessive inheritance of POF. No changes were detected in mRNA expression or protein levels of MRPS22, in POF patient- derived fibroblasts. Also, defects in mitochondrial oxidative phosphorylation or rRNA levels were not detected, which suggests a non-bioenergetic or tissue-specific mitochondrial defect. Mouse Heterozygous Mrps22 knockout mice revealed no signs of abnormalities and were fertile. Embryonic lethality was observed in heterozygous Mrps22 knockout mice. Drosophila The mRpS22 deficiency in ovarian somatic cells had no effect on fertility, whereas mRpS22 deficiency in germ cells resulted in absence of gametes and infertility, demonstrating a cell- autonomous requirement for mRpS22 in development of germ cell. Ding et al. (2019) Human mt-tRNA Mitochondrial dysfunction, lower level of ATP production, and high levels of ROS were detected in POF patients carrying mt-tRNA mutations including the A4435G (tRNAMet), C3303T (tRNALeu), G5821A (tRNACys), T4363C (tRNAGln), and A15951G (tRNATh). These mt-tRNA mutations may have active roles in the pathogensis and progression of POF. POF, premature ovarian failure; POLG, Mitochondrial DNA polymerase γ; PEO, progressive external ophthalmoplegia; mtDNA, mitochondrial DNA; MT-CO1, mitochondrial cytochrome c oxidase 1 gene; COX; cytochrome c oxidase; MRPS22, mitochondrial ribosomal protein S22; mt-tRNA, mitochondrial tRNA. 4 Review The role of mitochondria in premature ovarian failure K. Khodamoradi et al. J Contemp Med Sci | Vol. 6, No. 1, January–February 2020: 1–7 carboxylase. This enzyme plays an important role in cataboliz- ing branched-chain amino acids, odd-chain fatty acids, choles- terol, and other metabolites.60 Lam et al. reported a 45-year-old patient who had been diagnosed with propionic acidemia and experienced severe renal failure and POF.61 Mitochondrial dysfunction and increased oxidative stress have been consid- ered as possible mechanisms for these complications.61 As a study on mice oocytes has demonstrated, there is an age-associated alteration in the expression patterns of genes involved in mitochondrial functions and oxidative stress.29 There have been several studies on the role of mitochondrial ROS in POF. Some mitochondrial mutations increase the ROS level and decrease ATP production in germ cells, and con- sequently lead to disruption of normal oogenesis and accel- erated germ cell apoptosis, ultimately leading to POF.62 As oocytes have greater number of mtDNA copies than any cell in the body, pathological levels of ROS cause mtDNA dam- age, and mitochondria with nucleotide DNA changes produce more free radicals.55 The results of several studies have shown that mutations in the ATPase 6 gene, which maintains mito- chondrial genome stability and integrity, are associated with excessive ROS production and several disorders.63,64 Venkatesh et al. found that the mutation of the mitochondrial ATPase6 gene can lead to a higher ROS level in ovarian cells. The high ROS level can damage the mtDNA and membrane as a result, and may cause premature cessation of ovarian function by interruption of cell growth, expansion of atresia, and eventu- ally germ cell apoptosis.59 Moreover, it has been shown that in patients with ovarian ageing and POF, the ROS level in granu- losa cells is extremely high.65 According to these findings, mitochondrial ROS produc- tion and oxidative stress may influence normal oogenesis and ovarian reserve through activation of the apoptotic process, increased follicular atresia, induction of ovarian inflamma- tion, and development of mtDNA disorders that can lead to POF. Approaches to Fertility Preservation in Patients with POF by Influencing the Function of Mitochondria Due to the cumulative adverse effects of POF over time, mak- ing a timely diagnosis and initiating appropriate strategies are important for managing the symptoms, supporting patients’ emotional needs, and reducing risk.3 Hormone replacement therapy is the most popular treatment for POF-related symp- toms, but there are some serious side-effects for this treatment, including increased risks for breast and endometrial cancers.66 Other treatments for POF involve influencing the function of mitochondria. Coenzyme Q10 is one of these treatments stud- ied by Ben-Meir and their colleagues in aged mice. The results of this study showed that Coenzyme Q10 supplementation could enhance the activity of mitochondria and amending the mitochondrial gene expression. Consequently, the Coenzyme Q10 supplementation can prevent depletion of ovarian reserve and POF.25 Antioxidants are another treatment that can postpone POF. Melatonin is known as a highly effective antioxidant and potent ROS scavenger67 that protects cells against oxidative stress and diminishes the harmful effects of ROS.68 Recently, it has been reported that melatonin may be beneficial for reducing and preventing POF in patients who receive chemo- therapy treatment.69 Melatonin improves POF by reducing oxi- dative stress damage that was mediated by the SIRT1 signaling pathway.70 Furthermore, it has been demonstrated that mela- tonin prevents primordial follicle depletion in cisplatin-treated mice through suppression of the phosphorylation of PTEN/ AKT/FOXO3a pathway members.71 Although, the specific mechanisms underlying the actions of melatonin protection against ovarian follicle death are not yet clearly understood, it is well-known that its antioxidant effect can maintain the fol- licular morphology and growth, and can affect oxidative stress response by influencing ROS and glutathione production, mitochondrial activity, and apoptosis in follicular cells.67,72 Studies have shown that the use of herbal medicine is especially important in POF.73–75 Cistanches Herba is a para- sitic plant that is used in traditional Chinese medicine (TCM)76 for treatment of different diseases including female infertility by increasing sex hormone levels, though the exact regulat- ing mechanisms are unknown.77 Cistanches Herba can pre- vent cisplatin-induced apoptosis which causes POF in mice. Cistanches Herba upregulated mitofusin-2 (a mitochondria dynamin-like GTPase) expression and altered mitochondrial membrane structure via interaction with Bcl-2/Bax proteins.78 Dendrobium officinal polysaccharides (DOP), which are one of the main active components of Dendrobium officinal, another TCM, has recently been found to show good efficacy in producing anti-oxidative and anti-inflammatory effects75,79 and may have the potential to the treatment of POF. Wu et al. found that DOP improves the function of mitochondria, thus increasing the body’s antioxidant capacity and protecting the body from POF effects on mice. Their results also have shown that DOP could decrease the symptoms of POF, by increasing the body’s antioxidant capacity, balancing inflammation, and improving mitochondrial function. The potential mechanism signaling pathway may work through regulating the nuclear factor-κB and p53/Bcl-2.80 Zuogui Pills (ZGP) are a component in TCM used in the treatment of POF, increasing proliferation and decreasing apoptosis in the ovarian cells.81 The therapeu- tic effects of ZGP on the treatment of POF due to chemother- apy were investigated by Peng et al. They illustrated that the number of follicles, ovarian ultrastructures, and the estrous cycle notably ameliorated in rats with POF. Furthermore, ZGP increased the FSH levels and decreased estradiol levels in serum. Moreover, it declines Bax, cytochrome c (Cyt-c) on both gene and protein levels and elevates Bcl-2 gene expres- sion and protein levels. They proposed that ZPG can mediate POF through the balance of Bax/Bcl-2 in ovaries and suppres- sion of mitochondria-dependent apoptosis.75 Women with early identified ovarian ageing can have good reproductive potential, and spontaneous pregnancy remains a choice for women with adequate ovarian reserve who are ready to have a child.4 There are a number of treat- ment options available for women who are infertile due to POF which include ovarian cortical tissue cryopreserva- tion, oocyte, or embryo cryopreservation; oocyte, or embryo donation; and adoption. These treatment options can recom- mended before or during ovarian failure.82 Since mitochon- dria act as a vehicle for mtDNA transmission to subsequent generations, evaluation of mitochondrial disorders prior to any protocol of oocyte reconstruction would allow selection of healthy fertilizable oocytes.83 Although, Kasteren et al. ana- lyzed the incidence of familial cases of POF and concluded that 5 Review The role of mitochondria in premature ovarian failureK. Khodamoradi et al. J Contemp Med Sci | Vol. 6, No. 1, January–February 2020: 1–7 in these families the risk of other females developing POF will depend on the modes of inheritance and transmission, and further demonstrated that mitochondrial inheritance is not one common mode among their studied families.84 However, different research teams found other conditions that can be investigated for finding occurrence of POF related to mito- chondrial genetic diseases, and showed a correlation between mitochondrial diseases and POF.9,48 It has been reported that mitochondrial transfer into an oocyte can lead to prevention of apoptosis in this cell and promotion of embryonic devel- opment.85,86 Mitochondrial supplementation of oocytes is a strategy for overcoming mtDNA deficiency and improving developmental competence. Furthermore, supplementation of oocytes exhibiting mtDNA deficiency with autologous mito- chondria can improve the outcome of in vitro fertilization.83 Conclusions The mitochondrial disorder is one of the critical agents in pre- mature menopause and the occurrence of POF. Mitochondrial ROS production and mitochondrial genetic disorders have been reported as causes of POF. Due to the cumulative adverse effects of POF over time, making a timely diagnosis and ini- tiating appropriate strategies are important for managing symptoms, supporting patients’ emotional needs , and reduc- ing risk. The early diagnosis of POF can provide the opportu- nity to make good reproductive decisions such as having kids earlier and freezing oocytes or embryos. Given the maternal inheritance of mtDNA, genetic testing should be performed to detect mtDNA mutations involved in POF before starting treatment strategies. If these mutations are present, healthy mitochondrial transfer during ART should be used to prevent the transmission of POF caused by the mtDNA mutation to the female offspring. A fuller understanding of the mitochon- drial role in POF could contribute to the better management of women with POF in the future. Future strategies aimed at treatment of POF-related infertility should take into account the significance of the oocyte mitochondrial role in the occur- rence of this disorder. Conflict of interest All authors declare that there is no known conflict of interest regarding this publication. References 1. Jankowska K. Premature ovarian failure. Przeglad menopauzalny= Menopause Rev.. 2017;16(2):51. 2. Conway G, Hettiarachchi S, Murray A, Jacobs P. Fragile X premutations in familial premature ovarian failure. Lancet. 1995;346(8970):309-10. 3. Beck-Peccoz P, Persani L. Premature ovarian failure. Orphanet J. Rare Dis. 2006;1(1):9. 4. Maclaran K, Nikolaou D. Early ovarian ageing. Obstetr. Gynaecol. 2019;21(2):107-16. 5. Santoro N. Mechanisms of Premature Ovarian Failure. 2003. 6. May-Panloup P, Boucret L, Chao de la Barca J-M, Desquiret-Dumas V, Ferre- L’Hotellier V, Moriniere C, et al. Ovarian ageing: The role of mitochondria in oocytes and follicles. Human Reprod. Update. 2016;22(6):725-43. 7. Goswami D, Conway GS. Premature ovarian failure. Human Reprod. Update. 2005;11(4):391-410. 8. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429(6990):417. 9. Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: clinical and molecular genetic study. Lancet. 2004;364(9437):875-82. 10. Kujoth GC, Hiona A, Pugh T, Someya S, Panzer K, Wohlgemuth S, et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005;309(5733):481-4. 11. Pagnamenta AT, Taanman J-W, Wilson CJ, Anderson NE, Marotta R, Duncan AJ, et al. Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Human Reprod. 2006;21(10):2467-73. 12. May-Panloup P, Chretien M, Jacques C, Vasseur C, Malthiery Y, Reynier P. Low oocyte mitochondrial DNA content in ovarian insufficiency. Human Reprod. 2005;20(3):593-7. 13. Santos TA, El Shourbagy S, John JCS. Mitochondrial content reflects oocyte variability and fertilization outcome. Fertil. Steril. 2006;85(3):584-91. 14. Bonomi M, Somigliana E, Cacciatore C, Busnelli M, Rossetti R, Bonetti S, et al. Blood cell mitochondrial DNA content and premature ovarian aging. PLoS One. 2012;7(8):e42423. 15. Zheng H, Yu W-M, Shen J, Kang S, Hambardzumyan D, Li JY, et al. Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development. Sci. Adv. 2018;4(10):eaat2681. 16. Zhang X, Wu XQ, Lu S, Guo YL, Ma X. Deficit of mitochondria-derived ATP during oxidative stress impairs mouse MII oocyte spindles. Cell Res. 2006;16(10):841. 17. May‐Panloup P, Chretien MF, Malthiery Y, Reynier P. Mitochondrial DNA in the oocyte and the developing embryo. Curr. Topics Dev. Biol. 2007;77:51- 83. 18. Van Blerkom J, Davis PW, Lee J. Fertilization and early embryolgoy: ATP content of human oocytes and developmental potential and outcome after in-vitro fertilization and embryo transfer. Human Reprod. 1995;10(2):415-24. 19. Dumollard R, Duchen M, Carroll J. The role of mitochondrial function in the oocyte and embryo. Curr. Topics Dev. Biol. 2007;77:21-49. 20. Wai T, Ao A, Zhang X, Cyr D, Dufort D, Shoubridge EA. The role of mitochondrial DNA copy number in mammalian fertility. Biol. Reprod. 2010;83(1):52-62. 21. Brevini TA, Vassena R, Francisci C, Gandolfi F. Role of adenosine triphosphate, active mitochondria, and microtubules in the acquisition of developmental competence of parthenogenetically activated pig oocytes. Biol. Reprod. 2005;72(5):1218-23. 22. Yu Y, Dumollard R, Rossbach A, Lai FA, Swann K. Redistribution of mitochondria leads to bursts of ATP production during spontaneous mouse oocyte maturation. J. Cell. Physiol. 2010;224(3):672-80. 23. Aiken CE, Tarry-Adkins JL, Penfold NC, Dearden L, Ozanne SE. Decreased ovarian reserve, dysregulation of mitochondrial biogenesis, and increased lipid peroxidation in female mouse offspring exposed to an obesogenic maternal diet. FASEB J. 2015;30(4):1548-56. 24. Meldrum DR, Casper RF, Diez-Juan A, Simon C, Domar AD, Frydman R. Aging and the environment affect gamete and embryo potential: Can we intervene? Fertil. Steril. 2016;105(3):548-59. 25. Ben‐Meir A, Burstein E, Borrego‐Alvarez A, Chong J, Wong E, Yavorska T, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell. 2015;14(5):887-95. 26. Chan C, Liu V, Lau E, Yeung W, Ng E, Ho P. Mitochondrial DNA content and 4977 bp deletion in unfertilized oocytes. Mol. Human Reprod. 2005;11(12):843-6. 27. Duran HE, Simsek-Duran F, Oehninger SC, Jones Jr HW, Castora FJ. The association of reproductive senescence with mitochondrial quantity, function, and DNA integrity in human oocytes at different stages of maturation. Fertil. Steril. 2011;96(2):384-8. 28. Murakoshi Y, Sueoka K, Takahashi K, Sato S, Sakurai T, Tajima H, et al. Embryo developmental capability and pregnancy outcome are related to the mitochondrial DNA copy number and ooplasmic volume. J. Assist. Reprod. Genet. 2013;30(10):1367-75. 29. Hamatani T, Falco G, Carter MG, Akutsu H, Stagg CA, Sharov AA, et al. Age- associated alteration of gene expression patterns in mouse oocytes. Human Mol. Genet. 2004;13(19):2263-78. 6 Review The role of mitochondria in premature ovarian failure K. Khodamoradi et al. J Contemp Med Sci | Vol. 6, No. 1, January–February 2020: 1–7 30. Tiwari M, Prasad S, Tripathi A, Pandey AN, Ali I, Singh AK, et al. Apoptosis in mammalian oocytes: a review. Apoptosis. 2015;20(8):1019-25. 31. Aitken RJ, Findlay JK, Hutt KJ, Kerr JB. Apoptosis in the germ line. Reproduction (Cambridge, England). 2011;141(2):139-50. 32. Hussein MR, Haemel AK, Wood GS. Apoptosis and melanoma: molecular mechanisms. J. Pathol. J. Pathol. Soc. Great Br. Ireland. 2003;199(3):275-88. 33. Lu J, Sharma LK, Bai Y. Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis. Cell Res. 2009;19(7):802. 34. Lynch M, Koskella B, Schaack S. Mutation pressure and the evolution of organelle genomic architecture. Science. 2006;311(5768):1727-30. 35. Krakauer DC, Mira A. Mitochondria and germ-cell death. Nature. 1999;400(6740):125. 36. Ding Y, Xia B, Yu J, Leng J, Huang J. Mitochondrial DNA mutations and essential hypertension. Int. J. Mol. Med. 2013;32(4):768-74. 37. Yarham JW, Elson JL, Blakely EL, McFarland R, Taylor RW. Mitochondrial tRNA mutations and disease. Wiley Interdisc. Rev. RNA. 2010;1(2):304-24. 38. Ding Y, Xia B-H, Zhuo G-C, Zhang C-J, Leng J-H. Premature ovarian insufficiency may be associated with the mutations in mitochondrial tRNA genes. Endocr. J. 2019;66(1):81-8. 39. Kaguni LS. DNA polymerase γ, the mitochondrial replicase. Annu. Rev. Biochem. 2004;73(1):293-320. 40. Chan SS, Copeland WC. DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. Biochim. Biophy. Acta (BBA)-Bioenerg. 2009;1787(5):312-9. 41. Van Goethem G, Dermaut B, Löfgren A, Martin J-J, Van Broeckhoven C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat. Genet. 2001;28(3):211. 42. Stumpf JD, Saneto RP, Copeland WC. Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb. Perspect. Biol. 2013;5(4):a011395. 43. Tong Z-B, Sullivan SD, Lawless LM, Vanderhoof V, Zachman K, Nelson LM. Five mutations of mitochondrial DNA polymerase-gamma (POLG) are not a prevalent etiology for spontaneous 46, XX primary ovarian insufficiency. Fertil. Steril. 2010;94(7):2932-4. 44. Brauner R, Pierrepont S, Bignon-Topalovic J, McElreavey K, Bashamboo A. Etiology of primary ovarian insufficiency in a series young girls presenting at a pediatric endocrinology center. Eur. J. Pediatr. 2015;174(6):767-73. 45. Chen A, Tiosano D, Guran T, Baris HN, Bayram Y, Mory A, et al. Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency. Human Mol. Genet. 2018;27(11):1913-26. 46. Rzheshevsky A. Decrease in ATP biosynthesis and dysfunction of biological membranes. Two possible key mechanisms of phenoptosis. Biochemistry (Moscow). 2014;79(10):1056-68. 47. Thouas GA, Trounson AO, Wolvetang EJ, Jones GM. Mitochondrial dysfunction in mouse oocytes results in preimplantation embryo arrest in vitro. Biol. Reprod. 2004;71(6):1936-42. 48. Zhen X, Wu B, Wang J, Lu C, Gao H, Qiao J. Increased incidence of mitochondrial cytochrome C oxidase 1 gene mutations in patients with primary ovarian insufficiency. PLoS One. 2015;10(7):e0132610. 49. Wang T, Zhang M, Jiang Z, Seli E. Mitochondrial dysfunction and ovarian aging. Am. J. Reprod. Immunol. 2017;77(5):e12651. 50. Prasad S, Tiwari M, Pandey AN, Shrivastav TG, Chaube SK. Impact of stress on oocyte quality and reproductive outcome. J. Biomed. Sci. 2016;23(1):36. 51. Khodamoradi K, Amini-Khoei H, Khosravizadeh Z, Hosseini SR, Dehpour AR, Hassanzadeh G. Oxidative stress, inflammatory reactions and apoptosis mediated the negative effect of chronic stress induced by maternal separation on the reproductive system in male mice. Reprod. Biol. 2019;19(4):340-8. 52. Khodamoradi K, Amini-Khoei H, Khosravizadeh Z, Hosseini SR, Dehpour AR, Hassanzadeh G. Maternal separation can affect the reproductive system by inflammasome activation in female mice. J. Contemp. Med. Sci. 2019;5(3). 53. Behrman HR, Kodaman PH, Preston SL, Gao S. Oxidative stress and the ovary. J. Soc. Gynecol. Investig. 2001;8(1_suppl):S40-S2. 54. Amidi F, Rashidi Z, Khosravizadeh Z, Khodamoradi K, Talebi A, Navid S, et al. Antioxidant effects of quercetin in freeze-thawing process of mouse spermatogonial stem cells. Asian Pac. J. Reprod. 2019;8(1):7. 55. John JCS, Cooke ID, Barratt CL. Mitochondrial mutations and male infertility. Nat. Med. 1997;3(2):124-5. 56. Lu J, Wang Z, Cao J, Chen Y, Dong Y. A novel and compact review on the role of oxidative stress in female reproduction. Reprod. Biol. Endocrinol. 2018;16(1):80. 57. Bhardwaj JK, Mittal M, Saraf P, Kumari P. Pesticides induced oxidative stress and female infertility: A review. Toxin Rev. 2018:1-13. 58. Simpson JL. Genetic and phenotypic heterogeneity in ovarian failure: overview of selected candidate genes. Ann. NY Acad. Sci. 2008;1135(1):146-54. 59. Venkatesh S, Kumar M, Sharma A, Kriplani A, Ammini A, Talwar P, et al. Oxidative stress and ATPase6 mutation is associated with primary ovarian insufficiency. Arch. Gynecol. Obstet. 2010;282(3):313-8. 60. Chalmers R, Lawson A. Disorders of propionate and methylmalonate metabolism. Organic Acids in Man: Springer; 1982. p. 296-331. 61. Lam C, Desviat LR, Perez-Cerdá C, Ugarte M, Barshop BA, Cederbaum S. 45-Year-old female with propionic acidemia, renal failure, and premature ovarian failure; late complications of propionic acidemia? Mol. Genet. Metab. 2011;103(4):338-40. 62. Kumar M, Pathak D, Kriplani A, Ammini A, Talwar P, Dada R. Nucleotide variations in mitochondrial DNA and supra-physiological ROS levels in cytogenetically normal cases of premature ovarian insufficiency. Arch. Gynecol. Obstet. 2010;282(6):695-705. 63. Baracca A, Sgarbi G, Mattiazzi M, Casalena G, Pagnotta E, Valentino ML, et al. Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993. Biochim. Biophys. Acta (BBA)-Bioenerg. 2007;1767(7):913-9. 64. Venkatesh S, Deecaraman M, Kumar R, Shamsi M, Dada R. Role of reactive oxygen species in the pathogenesis of mitochondrial DNA (mtDNA) mutations in male infertility. Ind. J. Med. Res. 2009;129(2). 65. Ernst EH, Lykke-Hartmann K. Transcripts encoding free radical scavengers in human granulosa cells from primordial and primary ovarian follicles. J. Assist. Reprod. Genet. 2018;35(10):1787-98. 66. La Vecchia C. Hormone Replacement Therapy, Breast and Endometrial Cancer. 1996. 67. Gao C, Han HB, Tian XZ, Tan DX, Wang L, Zhou GB, et al. Melatonin promotes embryonic development and reduces reactive oxygen species in vitrified mouse 2‐cell embryos. J. Pineal Res. 2012;52(3):305-11. 68. Barberino RS, Menezes VG, Ribeiro AE, Palheta Jr RC, Jiang X, Smitz JE, et al. Melatonin protects against cisplatin-induced ovarian damage in mice via the MT1 receptor and antioxidant activity. Biol. Reprod. 2017;96(6):1244-55. 69. Jang H, Hong K, Choi Y. Melatonin and fertoprotective adjuvants: prevention against premature ovarian failure during chemotherapy. Int. Jo. Mol. Sci. 2017;18(6):1221. 70. Ma M, Chen X-Y, Li B, Li X-T. Melatonin protects premature ovarian insufficiency induced by tripterygium glycosides: role of SIRT1. Am. J. Transl. Res. 2017;9(4):1580. 71. Jang H, Lee OH, Lee Y, Yoon H, Chang EM, Park M, et al. Melatonin prevents cisplatin‐induced primordial follicle loss via suppression of PTEN/AKT/FOXO 3a pathway activation in the mouse ovary. J. Pineal Res. 2016;60(3):336-47. 72. Tamura H, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee L, et al. The role of melatonin as an antioxidant in the follicle. J. Ovar. Res. 2012;5(1):5. 73. DING Q, SHANG F-f. Meta-analysis of premature ovarian failure treated combined Chinese and Western medicines. J. Trad. Chin. Med. Univ. Hunan. 2011;9. 74. Kou M-J, Ding X-F, Chen J-X, Liu Y, Liu Y-Y. Traditional Chinese medicine combined with hormone therapy to treat premature ovarian failure: A meta-analysis of randomized controlled trials. Afr. J. Trad. Complement. Altern. Med. 2016;13(5):160-9. 75. Peng H, Zeng L, Zhu L, Luo S, Xu L, Zeng L, et al. Zuogui Pills inhibit mitochondria-dependent apoptosis of follicles in a rat model of premature ovarian failure. J. Ethnopharmacol. 2019;238:111855. 76. Li Z, Lin H, Gu L, Gao J, Tzeng C-M. Herba Cistanche (Rou Cong-Rong): One of the best pharmaceutical gifts of traditional Chinese medicine. Front. Pharmacol. 2016;7:41. 77. Li X, Yang S, Lv X, Sun H, Weng J, Liang Y, et al. The mechanism of mesna in protection from cisplatin-induced ovarian damage in female rats. J. Gynecol. Oncol. 2013;24(2):177-85. 78. Pan P, Wang Y, Leng X, Deng J, Wang C. Protective effects of cistanches herba aqueous extract on cisplatin-induced premature ovarian failure in mice. Afr. J. Trad. Complement. Altern. Med. 2017;14(6):90-101. 79. Luo D, Qu C, Lin G, Zhang Z, Xie J, Chen H, et al. Character and laxative activity of polysaccharides isolated from Dendrobium officinale. J. Funct. Foods. 2017;34:106-17. 80. Wu Y-y, Liang C-y, Liu T-t, Liang Y-m, Li S-j, Lu Y-y, et al. Protective roles and mechanisms of polysaccharides from Dendrobium officinal on natural aging-induced premature ovarian failure. Biomed. Pharmacother. 2018;101:953-60. 81. Yao Z, Wan Q, Lu H, Liu X. Effects of Zuogui pill, Yougui pill and relative compositions on differentiation towards germ cells of mouse embryonic stem cell 1B10. Zhongguo Zhong yao za zhi= Zhongguo zhongyao zazhi= China J. Chin. Mater. Med. 2015;40(3):495-500. 7 Review The role of mitochondria in premature ovarian failureK. Khodamoradi et al. J Contemp Med Sci | Vol. 6, No. 1, January–February 2020: 1–7 82. Blumenfeld Z, Hoek, Skillern, Goswami, Krauss, Chen, et al. Fertility treatment in women with premature ovarian failure. Expert Rev. Obstet. Gynecol. 2011;6(3):321-30. 83. El Shourbagy SH, Spikings EC, Freitas M, St John JC. Mitochondria directly influence fertilisation outcome in the pig. Reproduction. 2006;131(2):233- 45. 84. Van Kasteren Y, Hundscheid R, Smits A, Cremers F, Van Zonneveld P, Braat D. Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease? Human Reprod. 1999;14(10):2455-9. 85. Perez GI, Trbovich AM, Gosden RG, Tilly JL. Reproductive biology: mitochondria and the death of oocytes. Nature. 2000;403(6769):500. 86. Cagnone GL, Tsai T-S, Makanji Y, Matthews P, Gould J, Bonkowski MS, et al. Restoration of normal embryogenesis by mitochondrial supplementation in pig oocytes exhibiting mitochondrial DNA deficiency. Scient. Rep. 2016;6:23229. 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