2. Academic Validation
  3. BNC1 deficiency-triggered ferroptosis through the NF2-YAP pathway induces primary ovarian insufficiency

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

  • Nat Commun. 2022 Oct 5;13(1):5871. doi: 10.1038/s41467-022-33323-8.
Feixia Wang # 1,  Yifeng Liu # 1,  Feida Ni # 1,  Jiani Jin 1,  Yiqing Wu 1,  Yun Huang 1,  Xiaohang Ye 1,  Xilin Shen 2,  Yue Ying 1,  Jianhua Chen 3,  Ruixue Chen 1,  Yanye Zhang 1,  Xiao Sun 1,  Siwen Wang 1 4,  Xiao Xu 1,  Chuan Chen 1,  Jiansheng Guo 5,  Dan Zhang 6 7
Affiliations

Affiliations

  • 1 Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Zhejiang, 310006, China.
  • 2 College of Computer Science and Technology, Zhejiang University, Zhejiang, 310027, PR China.
  • 3 Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Zhejiang, 310006, People's Republic of China.
  • 4 Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02215, USA.
  • 5 Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou, Zhejiang, China.
  • 6 Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Zhejiang, 310006, China. zhangdan@zju.edu.cn.
  • 7 Clinical Research Center on Birth Defect Prevention and Intervention of Zhejiang Province, Hangzhou, 310006, China. zhangdan@zju.edu.cn.
  • # Contributed equally.
PMID: 36198708 DOI: 10.1038/s41467-022-33323-8
Abstract

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.

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