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

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.