The role of mitochondria in premature ovarian failure: A review


  • Zahra Khosravizadeh Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Zahra Rashidi Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
  • Ali Talebi School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
  • Kajal Khodamoradi Department of Urology, University of Miami Miller School of Medicine, Miami, FL.USA.
  • Gholamreza Hassanzadeh Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.



Premature ovarian failure, Mitochondria, Infertility, low ovarian reserve


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 in 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 ART 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.


1. Jankowska K. Premature ovarian failure. Przeglad menopauzalny= Menopause review. 2017;16(2):51.
2. Conway G, Hettiarachchi S, Murray A, Jacobs P. Fragile X premutations in familial premature ovarian failure. The Lancet. 1995;346(8970):309-10.
3. Beck-Peccoz P, Persani L. Premature ovarian failure. Orphanet journal of rare diseases. 2006;1(1):9.
4. Maclaran K, Nikolaou D. Early ovarian ageing. The Obstetrician & Gynaecologist. 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 Reproduction Update. 2016;22(6):725-43.
7. Goswami D, Conway GS. Premature ovarian failure. Human reproduction 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. The 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 Reproduction. 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 reproduction. 2005;20(3):593-7.
13. Santos TA, El Shourbagy S, John JCS. Mitochondrial content reflects oocyte variability and fertilization outcome. Fertility and sterility. 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. Science advances. 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 research. 2006;16(10):841.
17. May‐Panloup P, Chretien MF, Malthiery Y, Reynier P. Mitochondrial DNA in the oocyte and the developing embryo. Current topics in developmental biology. 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 reproduction. 1995;10(2):415-24.
19. Dumollard R, Duchen M, Carroll J. The role of mitochondrial function in the oocyte and embryo. Current topics in developmental biology. 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. Biology of reproduction. 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. Biology of reproduction. 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. Journal of cellular physiology. 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. The FASEB Journal. 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? Fertility and sterility. 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. Molecular human reproduction. 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. Fertility and sterility. 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. Journal of assisted reproduction and genetics. 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 molecular genetics. 2004;13(19):2263-78.
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. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland. 2003;199(3):275-88.
33. Lu J, Sharma LK, Bai Y. Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis. Cell research. 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. International journal of molecular medicine. 2013;32(4):768-74.
37. Yarham JW, Elson JL, Blakely EL, McFarland R, Taylor RW. Mitochondrial tRNA mutations and disease. Wiley Interdisciplinary Reviews: 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. Endocrine journal. 2019;66(1):81-8.
39. Kaguni LS. DNA polymerase γ, the mitochondrial replicase. Annual review of biochemistry. 2004;73(1):293-320.
40. Chan SS, Copeland WC. DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. Biochimica Et Biophysica Acta (BBA)-Bioenergetics. 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. Nature genetics. 2001;28(3):211.
42. Stumpf JD, Saneto RP, Copeland WC. Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harbor perspectives in biology. 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. Fertility and sterility. 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. European journal of pediatrics. 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 molecular genetics. 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. Biology of reproduction. 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. American Journal of Reproductive Immunology. 2017;77(5):e12651.
50. Prasad S, Tiwari M, Pandey AN, Shrivastav TG, Chaube SK. Impact of stress on oocyte quality and reproductive outcome. Journal of biomedical science. 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. Reproductive biology. 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. Journal of Contemporary Medical Sciences. 2019;5(3).
53. Behrman HR, Kodaman PH, Preston SL, Gao S. Oxidative stress and the ovary. Journal of the Society for Gynecologic Investigation. 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 Pacific Journal of Reproduction. 2019;8(1):7.
55. John JCS, Cooke ID, Barratt CL. Mitochondrial mutations and male infertility. Nature medicine. 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. Reproductive Biology and Endocrinology. 2018;16(1):80.
57. Bhardwaj JK, Mittal M, Saraf P, Kumari P. Pesticides induced oxidative stress and female infertility: a review. Toxin Reviews. 2018:1-13.
58. Simpson JL. Genetic and phenotypic heterogeneity in ovarian failure: overview of selected candidate genes. Annals of the New York Academy of Sciences. 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. Archives of gynecology and obstetrics. 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? Molecular genetics and metabolism. 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. Archives of gynecology and obstetrics. 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. Biochimica Et Biophysica Acta (BBA)-Bioenergetics. 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. Indian Journal of Medical Research. 2009;129(2).
65. Ernst EH, Lykke-Hartmann K. Transcripts encoding free radical scavengers in human granulosa cells from primordial and primary ovarian follicles. Journal of assisted reproduction and genetics. 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. Journal of pineal research. 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. Biology of reproduction. 2017;96(6):1244-55.
69. Jang H, Hong K, Choi Y. Melatonin and fertoprotective adjuvants: prevention against premature ovarian failure during chemotherapy. International journal of molecular sciences. 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. American journal of translational research. 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. Journal of pineal research. 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. Journal of ovarian research. 2012;5(1):5.
73. DING Q, SHANG F-f. Meta-analysis of premature ovarian failure treated combined Chinese and Western medicines [J]. Journal of Traditional Chinese Medicine University of 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. African Journal of Traditional, Complementary and Alternative Medicines. 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. Journal of ethnopharmacology. 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. Frontiers in pharmacology. 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. Journal of gynecologic oncology. 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. African Journal of Traditional, Complementary and Alternative Medicines. 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. Journal of Functional 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. Biomedicine & Pharmacotherapy. 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 journal of Chinese materia medica. 2015;40(3):495-500.
82. Blumenfeld Z, Hoek, Skillern, Goswami, Krauss, Chen, et al. Fertility treatment in women with premature ovarian failure. Expert Review of Obstetrics & Gynecology. 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 Reproduction. 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. Scientific reports. 2016;6:23229.




How to Cite

Khosravizadeh, Z., Rashidi, Z., Talebi, A., Khodamoradi, K., & Hassanzadeh, G. (2020). The role of mitochondria in premature ovarian failure: A review. Journal of Contemporary Medical Sciences, 6(1), 1–7.

Most read articles by the same author(s)

1 2 > >>