TRIM28-Mediated Excessive Oxidative Stress Induces Cellular Senescence in Granulosa Cells and Contributes to Premature Ovarian Insufficiency In Vitro and In Vivo
Premature ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by the abnormal alteration of hormone levels such as FSH and E<sub>2</sub>. POI causes infertility, severe daily life disturbances, and long-term health risks. However, the underlying mechan...
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MDPI AG
2024-03-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/13/3/308 |
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| author | Chong Zhou Dandan Li Jinxia He Tao Luo Yiting Liu Yue Xue Jian Huang Liping Zheng Jia Li |
| author_facet | Chong Zhou Dandan Li Jinxia He Tao Luo Yiting Liu Yue Xue Jian Huang Liping Zheng Jia Li |
| author_sort | Chong Zhou |
| collection | DOAJ |
| description | Premature ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by the abnormal alteration of hormone levels such as FSH and E<sub>2</sub>. POI causes infertility, severe daily life disturbances, and long-term health risks. However, the underlying mechanism remains largely unknown. In this study, we found that POI is associated with the cellular senescence of ovarian granulosa cells, and TRIM28 mediates oxidative stress (OS)-induced cellular senescence in granulosa cells. Mechanistically, OS causes a decrease in TRIM28 protein levels in KGN cells. Subsequently, it triggers an increase in the levels of autophagy marker proteins ATG5 and LC3B-II, and the downregulation of P62. Abnormal autophagy induces an increase in the levels of cellular senescence markers γ-H2A.X, P16, and P21, provoking cellular senescence in vitro. The overexpression of ovarian TRIM28 through a microinjection of lentivirus attenuated autophagy, cellular senescence, and follicular atresia in the ovaries of POI mice and improved mouse fertility in vivo. Our study highlights the triggers for POI, where the reduction of TRIM28, which is regulated by reactive oxygen species, causes follicular atresia and POI via triggering autophagy and inducing granulosa cell senescence. Shedding light on TRIM28 may represent a potential intervention strategy for POI. |
| first_indexed | 2024-04-24T18:36:39Z |
| format | Article |
| id | doaj.art-62f3ca195c1949a9a6dd96d7c16dc590 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-04-24T18:36:39Z |
| publishDate | 2024-03-01 |
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| spelling | doaj.art-62f3ca195c1949a9a6dd96d7c16dc5902024-03-27T13:18:31ZengMDPI AGAntioxidants2076-39212024-03-0113330810.3390/antiox13030308TRIM28-Mediated Excessive Oxidative Stress Induces Cellular Senescence in Granulosa Cells and Contributes to Premature Ovarian Insufficiency In Vitro and In VivoChong Zhou0Dandan Li1Jinxia He2Tao Luo3Yiting Liu4Yue Xue5Jian Huang6Liping Zheng7Jia Li8School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, ChinaKey Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Jiangxi Medical College, Nanchang University, Nanchang 330031, ChinaReproductive Medical Center, Jiangxi Maternal and Child Health Hospital, Affiliated Maternal and Child Health Hospital of Nanchang University, Nanchang 330006, ChinaSchool of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, ChinaSchool of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, ChinaSchool of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, ChinaKey Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Jiangxi Medical College, Nanchang University, Nanchang 330031, ChinaKey Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Jiangxi Medical College, Nanchang University, Nanchang 330031, ChinaSchool of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, ChinaPremature ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by the abnormal alteration of hormone levels such as FSH and E<sub>2</sub>. POI causes infertility, severe daily life disturbances, and long-term health risks. However, the underlying mechanism remains largely unknown. In this study, we found that POI is associated with the cellular senescence of ovarian granulosa cells, and TRIM28 mediates oxidative stress (OS)-induced cellular senescence in granulosa cells. Mechanistically, OS causes a decrease in TRIM28 protein levels in KGN cells. Subsequently, it triggers an increase in the levels of autophagy marker proteins ATG5 and LC3B-II, and the downregulation of P62. Abnormal autophagy induces an increase in the levels of cellular senescence markers γ-H2A.X, P16, and P21, provoking cellular senescence in vitro. The overexpression of ovarian TRIM28 through a microinjection of lentivirus attenuated autophagy, cellular senescence, and follicular atresia in the ovaries of POI mice and improved mouse fertility in vivo. Our study highlights the triggers for POI, where the reduction of TRIM28, which is regulated by reactive oxygen species, causes follicular atresia and POI via triggering autophagy and inducing granulosa cell senescence. Shedding light on TRIM28 may represent a potential intervention strategy for POI.https://www.mdpi.com/2076-3921/13/3/308premature ovarian insufficiencygranulosa cellscellular senescenceoxidative stressautophagyTRIM28 |
| spellingShingle | Chong Zhou Dandan Li Jinxia He Tao Luo Yiting Liu Yue Xue Jian Huang Liping Zheng Jia Li TRIM28-Mediated Excessive Oxidative Stress Induces Cellular Senescence in Granulosa Cells and Contributes to Premature Ovarian Insufficiency In Vitro and In Vivo Antioxidants premature ovarian insufficiency granulosa cells cellular senescence oxidative stress autophagy TRIM28 |
| title | TRIM28-Mediated Excessive Oxidative Stress Induces Cellular Senescence in Granulosa Cells and Contributes to Premature Ovarian Insufficiency In Vitro and In Vivo |
| title_full | TRIM28-Mediated Excessive Oxidative Stress Induces Cellular Senescence in Granulosa Cells and Contributes to Premature Ovarian Insufficiency In Vitro and In Vivo |
| title_fullStr | TRIM28-Mediated Excessive Oxidative Stress Induces Cellular Senescence in Granulosa Cells and Contributes to Premature Ovarian Insufficiency In Vitro and In Vivo |
| title_full_unstemmed | TRIM28-Mediated Excessive Oxidative Stress Induces Cellular Senescence in Granulosa Cells and Contributes to Premature Ovarian Insufficiency In Vitro and In Vivo |
| title_short | TRIM28-Mediated Excessive Oxidative Stress Induces Cellular Senescence in Granulosa Cells and Contributes to Premature Ovarian Insufficiency In Vitro and In Vivo |
| title_sort | trim28 mediated excessive oxidative stress induces cellular senescence in granulosa cells and contributes to premature ovarian insufficiency in vitro and in vivo |
| topic | premature ovarian insufficiency granulosa cells cellular senescence oxidative stress autophagy TRIM28 |
| url | https://www.mdpi.com/2076-3921/13/3/308 |
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