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Chromosome Segregation-1-like Gene Participates in Ferroptosis in Human Ovarian Granulosa Cells via Nucleocytoplasmic
Luanqian Hu1,2, Tongtong Hong1,2, Yuheng He1,2
1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China.
Insights
Chromosome segregation-1-like gene (CSE1L) deficiency causes ferroptosis in ovarian cells, impacting oocyte maturation and contributing to premature ovarian insufficiency (POI). This discovery may enable ferroptosis inhibitor treatments for POI.
Area of Science:
- Reproductive Endocrinology
- Cellular Biology
- Genetics
Background:
- Premature ovarian insufficiency (POI) affects 3.5% globally, with genetic factors implicated in 23.5% of cases.
- Iron metabolism dysregulation is linked to reproductive disorders, but its role in POI is unclear.
- The chromosome segregation-1-like gene (CSE1L) was identified as a potential factor in POI etiology.
Purpose of the Study:
- To investigate the role of CSE1L in maintaining iron homeostasis and its potential link to POI.
- To elucidate the molecular mechanism by which CSE1L deficiency affects ovarian function.
- To explore the therapeutic potential of targeting ferroptosis in POI.
Main Methods:
- Targeted panel sequencing to identify pathogenic variants in CSE1L.
- Transmission electron microscopy to confirm ferroptosis in human granulosa cells.
- Co-immunoprecipitation and chromatin immunoprecipitation assays to study protein interactions and gene regulation.
- Assessment of oocyte maturation in response to CSE1L inhibition.
Main Results:
- A pathogenic homozygous variant in CSE1L was identified in POI patients.
- CSE1L deficiency induced ferroptosis in human granulosa cells.
- CSE1L directly interacts with FoxO1, regulating its nuclear accumulation and subsequent NCOA4 transcription.
- Inhibition of CSE1L impaired oocyte maturation, potentially via oxidative stress.
Conclusions:
- CSE1L plays a critical role in preventing ferroptosis in human ovarian granulosa cells through nucleocytoplasmic transport regulation.
- The CSE1L-FoxO1-NCOA4 pathway is a key molecular mechanism underlying CSE1L's role in POI development.
- Targeting ferroptosis may offer a novel therapeutic strategy for premature ovarian insufficiency.
Abstract:
Premature ovarian insufficiency (POI) is defined as the depletion of ovarian function before the age of 40 years. The global prevalence of POI is 3.5%. To date, genetic factors account for 23.5% of the etiology of POI. Herein, a previously uncharacterized pathogenic homozygous variant of the chromosome segregation-1-like gene (CSE1L) was identified in POI patients via targeted panel sequencing. It is reported that dysregulated iron metabolism is involved in many reproductive endocrine disorders; however, its precise role in POI remains obscure. In this study, we identified CSE1L as a potential candidate gene that plays an important role in maintaining iron homeostasis. Deficiency of CSE1L led to ferroptosis in human granulosa cells, which was confirmed by transmission electron microscopy. Mechanistically, coimmunoprecipitation identified the direct interaction between CSE1L and FoxO1. Inhibition of CSE1L led to the excessive accumulation of FoxO1 in the nucleus via nucleocytoplasmic transport. Then, FoxO1 bound to the promoter region of NCOA4 and promoted its transcription, which was verified by a chromatin immunoprecipitation assay. Moreover, inhibition of CSE1L in cumulus cell monolayer could impede oocyte maturation, which might be associated with oxidative stress. Consequently, our study first revealed that CSE1L participated in ferroptosis in human ovarian granulosa cells via nucleocytoplasmic transportation, which might be helpful in revealing the molecular mechanism of CSE1L in the development of POI. Importantly, these findings might provide new insights into the application of ferroptosis inhibitors in the treatment of POI.
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