2. Academic Validation
  3. METTL3 prevents granulosa cells mitophagy by regulating YTHDF2-mediated BNIP3 mRNA degradation due to arsenic exposure

METTL3 prevents granulosa cells mitophagy by regulating YTHDF2-mediated BNIP3 mRNA degradation due to arsenic exposure

  • Ecotoxicol Environ Saf. 2024 Nov 1:286:117233. doi: 10.1016/j.ecoenv.2024.117233.
Tuo Zhang 1,  Jin Niu 2,  Tianhe Ren 3,  Huan Lin 3,  Meina He 4,  Zhiyi Sheng 3,  Yuntong Tong 3,  Bangming Jin 3,  Yingmin Wu 3,  Jigang Pan 3,  Ziwen Xiao 5,  Bing Guo 6,  Zhengrong Wang 7,  Tengxiang Chen 8,  Wei Pan 9
Affiliations

Affiliations

  • 1 Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, China; Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550009, China; Department of Obstetrics and Gynecology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550009, China; Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China; Guizhou Institute of Precision Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang 550009, China; Center for Reproductive Medicine, Shandong University, Jinan 250012, China.
  • 2 Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550009, China; School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, China.
  • 3 Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, China.
  • 4 Engineering Research Center for Molecular Medicine, College of Basic Medical Science, Guizhou Medical University, Guiyang 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China; Guizhou Institute of Precision Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang 550009, China.
  • 5 Department of Obstetrics and Gynecology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550009, China.
  • 6 Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China. Electronic address: guobingbs@126.com.
  • 7 Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550009, China. Electronic address: 34228560@qq.com.
  • 8 Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China; Guizhou Institute of Precision Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang 550009, China. Electronic address: txch@gmc.edu.cn.
  • 9 Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550009, China; School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, China. Electronic address: 313831139@qq.com.
PMID: 39490100 DOI: 10.1016/j.ecoenv.2024.117233
Abstract

The ovary is an important reproductive and endocrine organ for the continuation of the species and the homeostasis of the body's internal environment. Arsenic exposure is a global public health problem. However, the damage to the ovaries caused by exposure to arsenic-contaminated drinking water from neonatal mice period remains unclear. Here, we showed that arsenic exposure resulted in reduced granulosa cell proliferation, diminished ovarian reserve, decreased oogenesis, and endocrine disruption in mice. Mechanistically, arsenic exposure decreased the protein level of METTL3 in granulosa cells. The m6A modification levels of Mitophagy regulated gene BNIP3 in 3'UTR region was decreased in arsenic exposed granulosa cells. Meanwhile, YTHDF2, which decays mRNA, bound to the 3'UTR region of BNIP3 was also decreased in arsenic exposed ovarian granulosa cells. Thus, BNIP3 mRNA becames more stable, and Mitophagy was increased. The excessive Mitophagy in granulosa cells led to endocrine disruption, follicular atresia and diminished ovarian reserve. In summary, our study reveals that METTL3-dependent m6A modification regulates granulosa cell Mitophagy and follicular atresia by targeting BNIP3 which are induced by arsenic exposure.

Keywords

Arsenic; Granulosa cells; M(6)A; Mitophagy; Ovary.

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