LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells
Abstract Premature ovarian insufficiency (POI), defined by early loss of ovarian activity before the age of 40 years, is the leading cause of infertility and systematic aging in women, posing a public health challenge worldwide. However, its molecular etiology and therapeutic options are still lacki...
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| Format: | Article |
| Language: | English |
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Wiley
2025-06-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202417717 |
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| author | Yujie Shang Yunjun Li Di Han Kun Deng Wei Gao Minghua Wu |
| author_facet | Yujie Shang Yunjun Li Di Han Kun Deng Wei Gao Minghua Wu |
| author_sort | Yujie Shang |
| collection | DOAJ |
| description | Abstract Premature ovarian insufficiency (POI), defined by early loss of ovarian activity before the age of 40 years, is the leading cause of infertility and systematic aging in women, posing a public health challenge worldwide. However, its molecular etiology and therapeutic options are still lacking. Here, leucine‐rich repeat containing 4 (LRRC4) is identified as a critical regulator of folliculogenesis expressed in granulosa cells (GCs), which contributes to ovarian reserve maintenance. LRRC4 deficiency triggers defective oocyte maturation and excessive follicular atresia through inhibition of GC differentiation and ultimately leads to POI. Mechanistically, LRRC4 balances mitochondrial fission and fusion to inhibit excessive mitophagy by promoting the K48‐linked ubiquitination degradation of Yes‐associated protein (YAP), thereby maintaining the metabolic homeostasis of mitochondrial aerobic respiration and glycolysis. Importantly, targeting LRRC4 normalized follicular development and ovarian function in POI model mice. In conclusion, these data reveal the novel pathogenesis of POI and suggest that LRRC4 is a potential target for the diagnosis and treatment of POI. |
| format | Article |
| id | doaj-art-54ace0b0aed847688748a81f96ba3d8f |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-54ace0b0aed847688748a81f96ba3d8f2025-08-20T02:10:19ZengWileyAdvanced Science2198-38442025-06-011223n/an/a10.1002/advs.202417717LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa CellsYujie Shang0Yunjun Li1Di Han2Kun Deng3Wei Gao4Minghua Wu5The Affiliated Cancer Hospital of Xiangya School of Medicine Hunan Cancer Hospital Central South University Changsha 410000 ChinaAffiliated Hospital of Hubei University of Chinese Medicine Wuhan 430061 ChinaThe First Affiliated Hospital of Henan University of Chinese Medicine Zhengzhou 450003 ChinaThe Key Laboratory of Carcinogenesis of the Chinese Ministry of Health The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education Cancer Research Institute School of Basic Medicine Central South University Changsha 410078 ChinaThe Key Laboratory of Carcinogenesis of the Chinese Ministry of Health The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education Cancer Research Institute School of Basic Medicine Central South University Changsha 410078 ChinaThe Affiliated Cancer Hospital of Xiangya School of Medicine Hunan Cancer Hospital Central South University Changsha 410000 ChinaAbstract Premature ovarian insufficiency (POI), defined by early loss of ovarian activity before the age of 40 years, is the leading cause of infertility and systematic aging in women, posing a public health challenge worldwide. However, its molecular etiology and therapeutic options are still lacking. Here, leucine‐rich repeat containing 4 (LRRC4) is identified as a critical regulator of folliculogenesis expressed in granulosa cells (GCs), which contributes to ovarian reserve maintenance. LRRC4 deficiency triggers defective oocyte maturation and excessive follicular atresia through inhibition of GC differentiation and ultimately leads to POI. Mechanistically, LRRC4 balances mitochondrial fission and fusion to inhibit excessive mitophagy by promoting the K48‐linked ubiquitination degradation of Yes‐associated protein (YAP), thereby maintaining the metabolic homeostasis of mitochondrial aerobic respiration and glycolysis. Importantly, targeting LRRC4 normalized follicular development and ovarian function in POI model mice. In conclusion, these data reveal the novel pathogenesis of POI and suggest that LRRC4 is a potential target for the diagnosis and treatment of POI.https://doi.org/10.1002/advs.202417717granulosa cellleucine rich repeat containing 4metabolic homeostasismitochondria dynamicspremature ovarian insufficiency |
| spellingShingle | Yujie Shang Yunjun Li Di Han Kun Deng Wei Gao Minghua Wu LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells Advanced Science granulosa cell leucine rich repeat containing 4 metabolic homeostasis mitochondria dynamics premature ovarian insufficiency |
| title | LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells |
| title_full | LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells |
| title_fullStr | LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells |
| title_full_unstemmed | LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells |
| title_short | LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells |
| title_sort | lrrc4 deficiency drives premature ovarian insufficiency by disrupting metabolic homeostasis in granulosa cells |
| topic | granulosa cell leucine rich repeat containing 4 metabolic homeostasis mitochondria dynamics premature ovarian insufficiency |
| url | https://doi.org/10.1002/advs.202417717 |
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