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Observation of Parthanatos Involvement in Diminished Ovarian Reserve Patients and Melatonin’s Protective Function Through Inhibiting ADP-Ribose (PAR) Expression and Preventing AIF Translocation into the Nucleus

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Abstract

Diminished ovarian reserve (DOR) is characterized by the depletion of the ovarian pool, which leads to reductions in oocyte quality and quantity. Studies have suggested that ovarian reserve or ovarian aging is tightly related to apoptosis. However, the cell death mechanism is not comprehensively understood. Parthanatos, a type of poly [ADP-ribose] polymerase 1(PARP1)-dependent and apoptosis-inducing factor (AIF)-mediated cell death, plays a crucial role in various disorders. In the present study, we aimed to investigate whether parthanatos is involved in the pathogenesis of DOR. We recruited 40 patients (20 DOR patients and 20 normal ovarian reserve (NOR) patients) and examined PAR expression and AIF translocation in their isolated cumulus GCs (granulosa cells) by fluorescence microscopy. Our results demonstrated that PAR expression and AIF nuclear translocation were significantly higher in cumulus GCs of DOR patients, suggesting that PARP1-dependent cell death may be associated with DOR pathophysiology. Moreover, we tested the protective function of melatonin on hydrogen peroxide (H2O2)-induced parthanatos in human ovarian cancer (IGROV1) cells. Our results demonstrated that H2O2 treatment of IGROV1 cells led to excessive protein PARylation and AIF translocation into the nuclei. Melatonin effectively inhibits PARylation, blocks translocation of AIF into the nucleus, and consequently decreases the risk of parthanatos in cumulus GCs.

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Data Availability

The dataset analyzed during the study is available upon request from the corresponding author.

Abbreviations

DOR:

diminished ovarian reserve

AIF:

apoptosis-inducing factor

PARP1:

dependent cell death (Poly(ADP-Ribose) polymerase 1)

ROS:

reactive oxygen species

IVF:

in vitro fertilization

GCs:

granulosa cells

SRCC:

Spearman rank correlation coefficient

NOR:

normal ovarian reserve

COC:

cumulus-oocyte complex

FF:

follicular fluid

AMH:

anti-Müllerian hormone

GL:

granulosa lutein cell

PAR:

poly(ADP-ribose)

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Acknowledgments

This study was supported by the clinic big data research funding of Central South University. We would like to thank the staff of Reproductive Medicine Center, Xiang-Ya Hospital, Central South University, Professor Xueqing Ba (Institute of Genetics and Cytology, Northeast Normal University, China), Dr Saeed Ahmad (English Language Institute, Jazan University, KSA and Dr Khishigt Dandarchuluun ( Department of Statistics and Econometrics, National University of Mongolia, Mongolia).

Funding

This project supported by the National Natural Science Foundation of China (Grant number #81571507, (http://nsfc.gov.cn/)) and the research foundation of the Chinese Scholarship Counsel (PhD scholarship for Dr. Enkhzaya Batnasan).

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Authors and Affiliations

  1. Center for Reproductive Medicine, Xiang-Ya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China

    Enkhzaya Batnasan, Shi Xie, Qiong Zhang & Yanping Li

  2. Clinical Research Center for Women’s Reproductive Health in Hunan Province, Changsha, Hunan Province, People’s Republic of China

    Enkhzaya Batnasan, Shi Xie, Qiong Zhang & Yanping Li

Authors
  1. Enkhzaya Batnasan
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  2. Shi Xie
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  3. Qiong Zhang
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  4. Yanping Li
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Contributions

EB performed sample collection and experiments, conceived the study idea and design, performed the statistics analyses, drafted the manuscript, and was a major contributor in writing the manuscript. QZ and JZ contributed substantially to the interpretation of the data and provided statistical support. LY supervised and coordinated the study and design, contributed to the interpretation of the data, and revised the manuscript. All authors confirmed the final version of the manuscript.

Corresponding author

Correspondence to Yanping Li.

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Competing Interests

The authors declare that they have no competing interests.

Ethical Approval

This study was reviewed and approved by Ethics Committee of Xiang-Ya Hospital, Central South University. The research was also approved through Chinese Clinical Trial (registration number #ChiCTR-OOC-16008391). Written informed consent was obtained from each patient before sample collection.

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Batnasan, E., Xie, S., Zhang, Q. et al. Observation of Parthanatos Involvement in Diminished Ovarian Reserve Patients and Melatonin’s Protective Function Through Inhibiting ADP-Ribose (PAR) Expression and Preventing AIF Translocation into the Nucleus. Reprod. Sci. 27, 75–86 (2020). https://doi.org/10.1007/s43032-019-00005-8

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