The Emerging Role of Lysine Succinylation in Ovarian Aging

Overview

Journal Reprod Biol Endocrinol

Publisher Biomed Central

Specialties Endocrinology
Reproductive Medicine

Date 2023 Apr 20

PMID 37081483

Authors

Meiling Le

Jia Li

Dalei Zhang

Yuan Yuan

Chong Zhou

Jinxia He

Jian Huang

Liaoliao Hu

Tao Luo

Liping Zheng

Affiliations

Soon will be listed here.

Abstract

Background: Ovarian aging is a process of decline in its reserve leading to ovary dysfunction and even reduced health quality in offspring. However, aging-related molecular pathways in the ovary remain obscure. Lysine succinylation (Ksuc), a newly post-translational modification (PTM), has been found to be broadly conserved in both eukaryotic and prokaryotic cells, and associated with multiple pathophysiological processes. There are no relevant reports revealing a link between the molecular mechanisms of ovarian aging and Ksuc.

Methods: The level of Ksuc in ovaries of aged and premature ovarian insufficiency (POI) mice were detected by immunoblotting and immunohistochemical. To further explore the role of Ksuc in ovarian aging, using in vitro mouse ovary tissue culture and an in vivo mouse model with changed Ksuc level.

Results: Increased Ksuc in ovaries of aged and POI mice and distribution of Ksuc in various types of mice ovarian cells and the high level of Ksuc in granulosa cells (GCs) were revealed. Histological assessments and hormone levels analyses showed that the high Ksuc level down-regulated the ovarian index and the anti-Müllerian hormone (AMH) and estrogen levels, and increased follicular atresia. Moreover, in the high Ksuc groups, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) intensities and the expression of Cleaved-caspase-3 increased and the expression of B-cell lymphoma-2 (Bcl-2) decreased together with positively-expressed P21, an aging-related marker. These results suggest that ovarian aging is likely associated with alteration in Ksuc.

Conclusion: The present study has identified Ksuc in mouse ovary and found that high Ksuc level most likely contributes to ovarian aging which is expected further investigation to provide new information for delaying physiological ovarian aging and treating pathological ovarian aging.

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References

Georgakilas A, Martin O, Bonner W . p21: A Two-Faced Genome Guardian. Trends Mol Med. 2017; 23(4):310-319. DOI: 10.1016/j.molmed.2017.02.001. View

Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y . An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem. 2002; 277(37):34287-94. DOI: 10.1074/jbc.M204973200. View

Liu C, Yin H, Jiang H, Du X, Wang C, Liu Y . Extracellular Vesicles Derived from Mesenchymal Stem Cells Recover Fertility of Premature Ovarian Insufficiency Mice and the Effects on their Offspring. Cell Transplant. 2020; 29:963689720923575. PMC: 7586265. DOI: 10.1177/0963689720923575. View

Chon S, Umair Z, Yoon M . Premature Ovarian Insufficiency: Past, Present, and Future. Front Cell Dev Biol. 2021; 9:672890. PMC: 8141617. DOI: 10.3389/fcell.2021.672890. View

Fleming R, Seifer D, Frattarelli J, Ruman J . Assessing ovarian response: antral follicle count versus anti-Müllerian hormone. Reprod Biomed Online. 2015; 31(4):486-96. DOI: 10.1016/j.rbmo.2015.06.015. View

Hussein M . Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update. 2005; 11(2):162-77. DOI: 10.1093/humupd/dmi001. View

Hu L, Su T, Luo R, Zheng Y, Huang J, Zhong Z . Hippo pathway functions as a downstream effector of AKT signaling to regulate the activation of primordial follicles in mice. J Cell Physiol. 2018; 234(2):1578-1587. DOI: 10.1002/jcp.27024. View

Wei M, Li J, Yan H, Luo T, Huang J, Yuan Y . Physiological Ovarian Aging Is Associated with Altered Expression of Post-Translational Modifications in Mice. Int J Mol Sci. 2022; 23(1). PMC: 8744712. DOI: 10.3390/ijms23010002. View

Eissenberg J, Shilatifard A . Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Dev Biol. 2009; 339(2):240-9. PMC: 3711867. DOI: 10.1016/j.ydbio.2009.08.017. View

10.

Waghmare S, Samarin A, Samarin A, Danielsen M, Moller H, Policar T . Histone Acetylation Dynamics during In Vivo and In Vitro Oocyte Aging in Common Carp . Int J Mol Sci. 2021; 22(11). PMC: 8199789. DOI: 10.3390/ijms22116036. View

11.

Mohamed S, Shalaby S, Abdelaziz M, Brakta S, Hill W, Ismail N . Human Mesenchymal Stem Cells Partially Reverse Infertility in Chemotherapy-Induced Ovarian Failure. Reprod Sci. 2017; 25(1):51-63. PMC: 6344979. DOI: 10.1177/1933719117699705. View

12.

Otsuka F, McTavish K, Shimasaki S . Integral role of GDF-9 and BMP-15 in ovarian function. Mol Reprod Dev. 2011; 78(1):9-21. PMC: 3051839. DOI: 10.1002/mrd.21265. View

13.

Alleyn M, Breitzig M, Lockey R, Kolliputi N . The dawn of succinylation: a posttranslational modification. Am J Physiol Cell Physiol. 2017; 314(2):C228-C232. PMC: 5866436. DOI: 10.1152/ajpcell.00148.2017. View

14.

Hirschey M, Zhao Y . Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation. Mol Cell Proteomics. 2015; 14(9):2308-15. PMC: 4563717. DOI: 10.1074/mcp.R114.046664. View

15.

Li F, He X, Ye D, Lin Y, Yu H, Yao C . NADP(+)-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance. Mol Cell. 2015; 60(4):661-75. DOI: 10.1016/j.molcel.2015.10.017. View

16.

Xie Z, Dai J, Dai L, Tan M, Cheng Z, Wu Y . Lysine succinylation and lysine malonylation in histones. Mol Cell Proteomics. 2012; 11(5):100-7. PMC: 3418837. DOI: 10.1074/mcp.M111.015875. View

17.

Qian Y, Chen X . Tumor suppression by p53: making cells senescent. Histol Histopathol. 2010; 25(4):515-26. PMC: 2841029. DOI: 10.14670/HH-25.515. View

18.

Wang J, Liu B, Zhang C, Wang X, Zhen D, Huang X . Effects of icariin on ovarian function in d-galactose-induced aging mice. Theriogenology. 2018; 125:157-167. DOI: 10.1016/j.theriogenology.2018.10.028. View

19.

Pellatt L, Rice S, Dilaver N, Heshri A, Galea R, Brincat M . Anti-Müllerian hormone reduces follicle sensitivity to follicle-stimulating hormone in human granulosa cells. Fertil Steril. 2011; 96(5):1246-51.e1. DOI: 10.1016/j.fertnstert.2011.08.015. View

20.

Danilovich N, Babu P, Xing W, Gerdes M, Krishnamurthy H, Sairam M . Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice. Endocrinology. 2000; 141(11):4295-308. DOI: 10.1210/endo.141.11.7765. View