BNC1 deficiency-triggered ferroptosis through the NF2-YAP pathway induces primary ovarian insufficiency

• Published in: Nature communications Vol. 13; no. 1; p. 5871
• Main Authors: Wang, Feixia, Liu, Yifeng, Ni, Feida, Jin, Jiani, Wu, Yiqing, Huang, Yun, Ye, Xiaohang, Shen, Xilin, Ying, Yue, Chen, Jianhua, Chen, Ruixue, Zhang, Yanye, Sun, Xiao, Wang, Siwen, Xu, Xiao, Chen, Chuan, Guo, Jiansheng, Zhang, Dan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-10-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/51; 13/89; 14/19; 14/28; 14/63; 38/15; 38/47; 38/77; 38/90; 38/91; 42; 42/34; 45/88; 631/136/2434/1706; 631/443/494/2732/1577; 631/80/82/23; 64/60; 692/308/2056; 96/44; 96/95; 96/98; Basonuclin; Ferroptosis; Follicles; Gametocytes; Health risks; Homeostasis; Humanities and Social Sciences; Infertility; Lipid metabolism; Lipids; multidisciplinary; Mutation; Oocytes; Ovaries; Science; Science (multidisciplinary); Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33323-8

Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, severe daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We previously identified a Basonuclin 1 (
BNC1
) mutation from a large Chinese POI pedigree and found that mice with targeted
Bnc1
mutation exhibit symptoms of POI. In this study, we found that BNC1 plays key roles in ovarian reserve and maintaining lipid metabolism and redox homeostasis in oocytes during follicle development. Deficiency of BNC1 results in premature follicular activation and excessive follicular atresia. Mechanistically, BNC1 deficiency triggers oocyte ferroptosis via the NF2-YAP pathway. We demonstrated that pharmacologic inhibition of YAP signaling or ferroptosis significantly rescues
Bnc1
mutation-induced POI. These findings uncover a pathologic mechanism of POI based on BNC1 deficiency and suggest YAP and ferroptosis inhibitors as potential therapeutic targets for POI.
Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction that results in infertility. Here they show that BCN1 mutation results in premature ovarian follicle activation and atresia through dysregulation of ferroptosis.