Review

.2020 Nov:63:101168.

doi: 10.1016/j.arr.2020.101168. Epub 2020 Sep 4.

Mitochondria in Ovarian Aging and Reproductive Longevity

Jasmine L Chiang¹, Pallavi Shukla², Kelly Pagidas³, Noha S Ahmed⁴, Srinivasu Karri⁵, Deidre D Gunn¹, William W Hurd¹, Keshav K Singh⁶

Affiliations

¹ Division of Reproductive Endocrinology & Infertility, University of Alabama at Birmingham, 1700 6(th)Avenue South, Birmingham, AL, 35233, United States.
² Department of Genetics, University of Alabama at Birmingham, Kaul Genetics Building Room 630, 720 20(th)Street South, Birmingham, AL, 35294, United States; Department of Molecular Endocrinology, National Institute for Research in Reproductive Health (NIRRH), Jehangir Merwanji Street, Parel, Mumbai, 400012, India.
³ Department of Reproductive Medicine, TCM University, 9 Jason Drive, Lincoln, RI, 02865, United States.
⁴ Department of Genetics, University of Alabama at Birmingham, Kaul Genetics Building Room 630, 720 20(th)Street South, Birmingham, AL, 35294, United States; Department of Dermatology, Zagazig University, 44519 Shaibet an Nakareyah, Zagazig 2, Ash Sharqia Governorate, Egypt.
⁵ Department of Genetics, University of Alabama at Birmingham, Kaul Genetics Building Room 630, 720 20(th)Street South, Birmingham, AL, 35294, United States.
⁶ Department of Genetics, University of Alabama at Birmingham, Kaul Genetics Building Room 630, 720 20(th)Street South, Birmingham, AL, 35294, United States; UAB Department of Genetics, Center for Women's Reproductive Health, Kaul Genetics Building University of Alabama at Birmingham, Room 620, 720 20(th)Street South, Birmingham, AL, 35294, United States. Electronic address: kksingh@uab.edu.

PMID:32896666
PMCID: PMC9375691
DOI: 10.1016/j.arr.2020.101168

Review

Mitochondria in Ovarian Aging and Reproductive Longevity

Jasmine L Chiang et al. Ageing Res Rev.2020 Nov.

.2020 Nov:63:101168.

doi: 10.1016/j.arr.2020.101168. Epub 2020 Sep 4.

Authors

Jasmine L Chiang¹, Pallavi Shukla², Kelly Pagidas³, Noha S Ahmed⁴, Srinivasu Karri⁵, Deidre D Gunn¹, William W Hurd¹, Keshav K Singh⁶

Affiliations

¹ Division of Reproductive Endocrinology & Infertility, University of Alabama at Birmingham, 1700 6(th)Avenue South, Birmingham, AL, 35233, United States.
² Department of Genetics, University of Alabama at Birmingham, Kaul Genetics Building Room 630, 720 20(th)Street South, Birmingham, AL, 35294, United States; Department of Molecular Endocrinology, National Institute for Research in Reproductive Health (NIRRH), Jehangir Merwanji Street, Parel, Mumbai, 400012, India.
³ Department of Reproductive Medicine, TCM University, 9 Jason Drive, Lincoln, RI, 02865, United States.
⁴ Department of Genetics, University of Alabama at Birmingham, Kaul Genetics Building Room 630, 720 20(th)Street South, Birmingham, AL, 35294, United States; Department of Dermatology, Zagazig University, 44519 Shaibet an Nakareyah, Zagazig 2, Ash Sharqia Governorate, Egypt.
⁵ Department of Genetics, University of Alabama at Birmingham, Kaul Genetics Building Room 630, 720 20(th)Street South, Birmingham, AL, 35294, United States.
⁶ Department of Genetics, University of Alabama at Birmingham, Kaul Genetics Building Room 630, 720 20(th)Street South, Birmingham, AL, 35294, United States; UAB Department of Genetics, Center for Women's Reproductive Health, Kaul Genetics Building University of Alabama at Birmingham, Room 620, 720 20(th)Street South, Birmingham, AL, 35294, United States. Electronic address: kksingh@uab.edu.

PMID:32896666
PMCID: PMC9375691
DOI: 10.1016/j.arr.2020.101168

Abstract

Mitochondrial dysfunction is one of the hallmarks of aging. Consistently mitochondrial DNA (mtDNA) copy number and function decline with age in various tissues. There is increasing evidence to support that mitochondrial dysfunction drives ovarian aging. A decreased mtDNA copy number is also reported during ovarian aging. However, the mitochondrial mechanisms contributing to ovarian aging and infertility are not fully understood. Additionally, investigations into mitochondrial therapies to rejuvenate oocyte quality, select viable embryos and improve mitochondrial function may help enhance fertility or extend reproductive longevity in the future. These therapies include the use of mitochondrial replacement techniques, quantification of mtDNA copy number, and various pharmacologic and lifestyle measures. This review aims to describe the key evidence and current knowledge of the role of mitochondria in ovarian aging and identify the emerging potential options for therapy to extend reproductive longevity and improve fertility.

Keywords: Infertility; Mitochondrial DNA; Mitochondrial dysfunction; Mitochondrial therapies; Ovarian aging; Reproductive longevity.

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Conflict of interest statement

Declaration of Competing Interest

The authors report no declarations of interest.

Figures

**Fig. 1.**
Representation of age-associated changes in the ovary and mitochondria. The aging process alters ovarian reserve (quantity) and oocyte competence (quality). Mitochondria demonstrate parallel changes, quantitatively and qualitatively. AMH, anti-Mullerian hormone; AFC, antral follicle count; FSH, follicle stimulating hormone; ROS, reactive oxygen species; IVF, in vitro fertilization; mtDNA, mitochondrial DNA; ATP, adenosine triphosphate; AGE, advanced glycation end-products.

**Fig. 2.**
Schematic diagram of physiologic changes in mtDNA copy number from oogonia to blastocyst embryo. A minimum threshold for mtDNA copy number is necessary in the oocyte for fertilization (approximately 4000 copies) and for post-implantation development (approximately 45,000 copies). After fertilization, the mtDNA copy number within each cell decreases until it reaches the blastocyst stage. Around implantation, mitochondrial replication resumes in the blastomeres and total mitochondrial DNA copy number increases. GV, germinal vesicle; MI, meiosis I oocyte; MII meiosis II (mature) oocyte.

**Fig. 3.**
Mammalian mitochondrial electron transport chain subunit composition of oxidative phosphorylation (OXPHOS) complexes encoded by mtDNA and nuclear DNA. MtDNA, mitochondrial DNA; NAD, nicotinamide adenine dinucleotide; FAD, flavin adenine dinucleotide; CoQ10, coenzyme Q10; Cyt C, cytochrome C; ADP, adenosine diphosphate; ATP, adenosine triphosphate; NRF, nuclear respiratory factor; PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; AMPK, adenosine monophosphate-activated protein kinase; SIRT3, sirtuin 3.

**Fig. 4.**
Mutation in these nuclear genes are associated with mitochondrial dysfunction and accelerated ovarian aging (mouse model). Mutations in these mitochondrial genes are associated with ovarian aging (multiple species). There is mitochondrial-to-nuclear crosstalk, which induces phenotypic effects on ovarian aging. ROS, Reactive Oxygen Species. bMT, bovine mitochondria; RNR, ribonucleotide reductase; ND1, NADH-ubiquinone oxidoreductase chain 1; cytochrome oxidase subunit 1; ATP, adenosine triphosphate; CYB, Cytochrome B.

**Fig. 5.**
Diagram of an ovarian preovulatory follicle depicting the cumulus oocyte complex and bidirectional crosstalk between cumulus granulosa cells and the oocyte, perturbation of which contributes to ovarian aging and infertility. FSH, follicle stimulating hormone; LH, luteinizing hormone; cGMP, cyclic guanosine monophosphate; BMP15, bone morphogenetic protein 15; GDF9, growth differentiation factor 9; MGC, mural granulosa cell; CGC, cumulus granulosa cell.

See this image and copyright information in PMC

References

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Mitochondria in Ovarian Aging and Reproductive Longevity

Affiliations

Mitochondria in Ovarian Aging and Reproductive Longevity

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources