Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep;32(9):3154-3165.
doi: 10.1007/s43032-025-01954-z. Epub 2025 Aug 12.

Melatonin Protects against LPS-Induced Mitochondrial Dyshomeostasis and Ovarian Damage through JNK Signaling Pathway in Mouse Ovary

Ling-Ge Shi #  1   2   3 , Si-Min Ding #  1   2 , Tong-Kun Guo #  4 , Peng Chen #  5 , Shuang-Shuang Cui  1   2   3 , Zhuo-Nan Yang  1   2   3 , Mengyao Wang  1   2   3 , Rui Wang  6 , Dongmei Ji  1   2   3 , Tao Zhang  7   8 , Dan Liang  1   2   3 , Lili Wang  9 , Yunxia Cao  10   11   12 , Yajing Liu  13   14   15
Affiliations

Melatonin Protects against LPS-Induced Mitochondrial Dyshomeostasis and Ovarian Damage through JNK Signaling Pathway in Mouse Ovary

Ling-Ge Shi et al. Reprod Sci. 2025 Sep.

Abstract

Both mitochondrial dysfunction and inflammation are closely associated with the pathogenesis of diminished ovarian reserve (DOR). While melatonin (MT) is known to protect against ovarian injury, its precise mechanism in counteracting lipopolysaccharide (LPS)-induced mitochondrial dysfunction and ovarian reserve impairment remains unclear. This study aimed to explore the effects and underlying mechanisms of MT on LPS-induced ovarian reserve dysfunction. Follicle development in mouse models was assessed using HE staining and follicle counting. Immunofluorescence, Western blotting, and quantitative real-time PCR were employed to investigate the biological mechanisms by which MT protects the ovary. The levels of reactive oxygen species (ROS) and mitochondrial function in KGN cells were evaluated using H2DCFDA and TMRE staining. The findings revealed that LPS stimulation led to reduced expression of anti-Mullerian hormone (AMH) and growth differentiation factor 9 (GDF9), indicating impaired ovarian function. Treatment with MT countered these effects. Immunofluorescence analysis demonstrated that MT alleviated LPS-induced follicular depletion and modulated the expression levels of mitochondrial dynamics-related proteins OPA1 and DRP1. Additionally, LPS exposure induced excessive autophagy, elevated ROS levels, and heightened inflammation but did not significantly affect cell cycle progression or apoptosis. Notably, MT rescued the suppression of the JNK pathway caused by LPS stimulation. In summary, our results indicate that MT effectively restores the balance between mitochondrial fusion and fission, enhances ovarian reserve function via activation of the JNK signaling pathway, suppresses inflammation and autophagy, and ultimately improves overall ovarian function.

Keywords: Diminished ovarian reserve; Excessive autophagy; JNK signaling pathway; LPS; Melatonin; Mitochondrial dyshomeostasis.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics Approval and Consent to Participate: The Anhui Medical University Experimental Animal Welfare and Ethics Committee approved the experimental protocol (No. LLSC20220752). The study involving mice was approved by the Ethical Review Committee of the Animal Experimentation Centre of Anhui Medical University. Conflict of interest: The authors have declared that no competing interests exist.

References

    1. Busnelli A, Somigliana E, Cirillo F, Levi-Setti PE. Is diminished ovarian reserve a risk factor for miscarriage? Results of a systematic review and meta-analysis. Hum Reprod Update. 2021;27:973–88. https://doi.org/10.1093/humupd/dmab018 . - DOI - PubMed
    1. Li H, Wang X, Mu H, Mei Q, Liu Y, Min Z, Zhang L, Su P, Xiang W. Mir-484 contributes to diminished ovarian reserve by regulating granulosa cell function via YAP1-mediated mitochondrial function and apoptosis. Int J Biol Sci. 2022;18:1008–21. https://doi.org/10.7150/ijbs.68028) . - DOI - PubMed - PMC
    1. Winship AL, Alesi LR, Stringer JM, Cao Y, Lewis YM, Tu L, Swindells EOK, Giridharan S, Cai X, Griffiths MJ, Zerafa N, Gilham L, Hickey M, Hutt KJ. Conditional loss of Brca1 in oocytes causes reduced litter size, ovarian reserve depletion and impaired oocyte in vitro maturation with advanced reproductive age in mice. EBioMedicine. 2024;106:105262. https://doi.org/10.1016/j.ebiom.2024.105262) . - DOI - PubMed - PMC
    1. Younis JS, Iskander R, Fauser B, Izhaki I. Does an association exist between menstrual cycle length within the normal range and ovarian reserve biomarkers during the reproductive years? A systematic review and meta-analysis. Hum Reprod Update. 2020;26:904–28. https://doi.org/10.1093/humupd/dmaa013) . - DOI - PubMed
    1. Yan J, Zhang X, Zhu K, Yu M, Liu Q, De Felici M, Zhang T, Wang J, Shen W. Sleep deprivation causes gut dysbiosis impacting on systemic metabolomics leading to premature ovarian insufficiency in adolescent mice. Theranostics. 2024;14:3760–76. https://doi.org/10.7150/thno.95197) . - DOI - PubMed - PMC

LinkOut - more resources