PDF(Pubmed)
Abstract：
Premature ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by the abnormal alteration of hormone levels such as FSH and E2. POI causes infertility, severe daily life disturbances, and long-term health risks. However, the underlying mechanism remains largely unknown. In this study, we found that POI is associated with the cellular senescence of ovarian granulosa cells, and TRIM28 mediates oxidative stress (OS)-induced cellular senescence in granulosa cells. Mechanistically, OS causes a decrease in TRIM28 protein levels in KGN cells. Subsequently, it triggers an increase in the levels of autophagy marker proteins ATG5 and LC3B-II, and the downregulation of P62. Abnormal autophagy induces an increase in the levels of cellular senescence markers γ-H2A.X, P16, and P21, provoking cellular senescence in vitro. The overexpression of ovarian TRIM28 through a microinjection of lentivirus attenuated autophagy, cellular senescence, and follicular atresia in the ovaries of POI mice and improved mouse fertility in vivo. Our study highlights the triggers for POI, where the reduction of TRIM28, which is regulated by reactive oxygen species, causes follicular atresia and POI via triggering autophagy and inducing granulosa cell senescence. Shedding light on TRIM28 may represent a potential intervention strategy for POI.
摘要：
过早卵巢功能不全（POI）是一种以FSH和E2等激素水平异常改变为特征的卵巢功能不全的临床综合征。POI导致不孕,严重的日常生活障碍，和长期健康风险。然而,潜在的机制在很大程度上仍然未知。在这项研究中,我们发现POI与卵巢颗粒细胞的衰老有关,TRIM28介导氧化应激（OS）诱导的颗粒细胞衰老。机械上,OS导致KGN细胞中TRIM28蛋白水平降低。随后，它触发自噬标记蛋白ATG5和LC3B-II的水平增加，以及P62的下调。异常的自噬诱导细胞衰老标志物γ-H2A的水平增加。X,P16和P21在体外引起细胞衰老。通过显微注射慢病毒减毒自噬过表达卵巢TRIM28,细胞衰老,和POI小鼠卵巢中的卵泡闭锁，并改善了小鼠体内的生育能力。我们的研究强调了POI的触发因素，其中TRIM28的还原是由活性氧调节的，通过触发自噬和诱导颗粒细胞衰老引起卵泡闭锁和POI。TRIM28上的发光可能代表了POI的潜在干预策略。
