2. Academic Validation
  3. Cryptochrome 1 regulates ovarian granulosa cell senescence through NCOA4-mediated ferritinophagy

Cryptochrome 1 regulates ovarian granulosa cell senescence through NCOA4-mediated ferritinophagy

  • Free Radic Biol Med. 2024 Mar 22:217:1-14. doi: 10.1016/j.freeradbiomed.2024.03.015.
Jing Ma 1,  Sixing Chen 2,  Jing Liu 3,  Yixin Liao 3,  Lina Li 3,  Chi Chiu Wang 4,  Sishi Song 5,  Rixuan Feng 6,  Haoyue Hu 7,  Song Quan 8
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong, China.
  • 2 Center for Reproductive Medicine, Foshan Women and Children Hospital, Foshan, Guangdong, China.
  • 3 Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 4 Department of Obstetrics and Gynaecology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong, China.
  • 5 School of Public Health, Southern Medical University, Guangzhou, Guangdong, China.
  • 6 School of Nursing, Southern Medical University, Guangzhou, Guangdong, China.
  • 7 Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: 471123018@qq.com.
  • 8 Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: quansong@smu.edu.cn.
PMID: 38522484 DOI: 10.1016/j.freeradbiomed.2024.03.015
Abstract

Age-associated decreases in follicle number and oocyte quality result in a decline in female fertility, which is associated with increased infertility. Granulosa cells play a major role in oocyte development and maturation both in vivo and in vitro. However, it is unclear whether a reduction in Cryptochrome 1 (Cry1) expression contributes to granulosa cell senescence, and further exploration is needed to understand the underlying mechanisms. In this study, we investigated the role of Cry1, a core component of the molecular circadian clock, in the regulation of senescence in ovarian granulosa cells. Western blotting and qRT-PCR showed that Cry1 expression was downregulated in aged human ovarian granulosa cells and was correlated with age and anti-Müllerian hormone (AMH) levels. RNA-seq analysis suggested that ferritinophagy was increased after Cry1 knockdown in KGN cells. MDA, iron, and Reactive Oxygen Species (ROS) assays were used to detect cellular ferritinophagy levels. Ferroptosis inhibitors, iron Chelators, Autophagy inhibitors, and nuclear receptor coactivator 4 (NCOA4) knockdown alleviated KGN cell senescence induced by Cry1 knockdown. Immunofluorescence, immunoprecipitation, and ubiquitination assays indicated that Cry1 affected NCOA4 ubiquitination and degradation through HERC2, thereby affecting NCOA4-mediated ferritinophagy and causing granulosa cell senescence. KL201, a Cry1 stabilizer, enhanced ovarian function in naturally aged mice by reducing ferritinophagy. Our study reveals the potential mechanisms of action of Cry1 during ovarian aging and provides new insights for the clinical treatment of age-related fertility decline.

Keywords

Cell senescence; Cry1; Ferritinophagy; Granulosa cells; NCOA4; Ovarian aging.

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