1. AMPK/mTOR downregulated autophagy enhances aberrant endometrial decidualization in folate‐deficient pregnant mice
- Author
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Junlin He, Yan Zhang, Rufei Gao, Xueqing Liu, Xinyi Mu, Lei Zhang, Qiutong Chen, Xuemei Chen, Yanqing Geng, Yingxiong Wang, and Yubin Ding
- Subjects
0301 basic medicine ,Physiology ,Clinical Biochemistry ,AMP-Activated Protein Kinases ,Folic Acid Deficiency ,Mice ,03 medical and health sciences ,Folic Acid ,0302 clinical medicine ,Pregnancy ,Autophagy ,Decidua ,Animals ,Medicine ,Cells, Cultured ,PI3K/AKT/mTOR pathway ,Endometrial Stromal Cell ,Cathepsin ,business.industry ,TOR Serine-Threonine Kinases ,Autophagosomes ,Decidualization ,AMPK ,Cell Biology ,Transfection ,In vitro ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Stromal Cells ,Lysosomes ,business ,Microtubule-Associated Proteins ,Signal Transduction - Abstract
Existing evidence suggests that adverse pregnancy outcomes are closely related to dietary factors. Folate plays an important role in neural tube formation and fetal growth, folate deficiency is a major risk factor of birth defects. Our early studies showed that folate deficiency could impair enddecidualization, however, the mechanism is still unclear. Dysfunctional autophagy is associated with many diseases. Here, we aimed to evaluate the adverse effect of folate deficiency on endometrial decidualization, with a particular focus on endometrial cell autophagy. Mice were fed with no folate diet in vivo and the mouse endometrial stromal cell was cultured in a folate-free medium in vitro. The decrease of the number of endometrial autophagosomes and the protein expressions of autophagy in the folate-deficient group indicated that autophagosome formation, autophagosome-lysosome fusion, and lysosomal degradation were inhibited. Autophagic flux examination using mCherry-GFP-LC3 transfection showed that the fusion of autophagosomes with lysosomes was inhibited by folate deficiency. Autophagy inducer rapamycin could reverse the impairment of folate deficiency on endometrial decidualization. Moreover, folate deficiency could reduce autophagy by disrupting AMPK/mTOR signaling, resulting in aberrant endometrial decidualization and adverse pregnancy outcomes. Further co-immunoprecipitation examination showed that decidual marker protein Hoxa10 could interact with autophagic marker protein Cathepsin L, and the interaction was notably reduced by folate deficiency. In conclusion, AMPK/mTOR downregulated autophagy was essential for aberrant endometrial decidualization in early pregnant mice, which could result in adverse pregnancy outcomes. This provided some new clues for understanding the causal mechanisms of birth defects induced by folate deficiency.
- Published
- 2021