Glutaminolysis regulates endometrial fibrosis in intrauterine adhesion via modulating mitochondrial function.

IF 4.3 2区 生物学 Q1 BIOLOGY Biological Research Pub Date : 2024-04-01 DOI:10.1186/s40659-024-00492-3
Pei Chen, Chaoshuang Ye, Yunke Huang, Bingning Xu, Tianyu Wu, Yuanhang Dong, Yang Jin, Li Zhao, Changchang Hu, Jingxia Mao, Ruijin Wu
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Abstract

Background: Endometrial fibrosis, a significant characteristic of intrauterine adhesion (IUA), is caused by the excessive differentiation and activation of endometrial stromal cells (ESCs). Glutaminolysis is the metabolic process of glutamine (Gln), which has been implicated in multiple types of organ fibrosis. So far, little is known about whether glutaminolysis plays a role in endometrial fibrosis.

Methods: The activation model of ESCs was constructed by TGF-β1, followed by RNA-sequencing analysis. Changes in glutaminase1 (GLS1) expression at RNA and protein levels in activated ESCs were verified experimentally. Human IUA samples were collected to verify GLS1 expression in endometrial fibrosis. GLS1 inhibitor and glutamine deprivation were applied to ESCs models to investigate the biological functions and mechanisms of glutaminolysis in ESCs activation. The IUA mice model was established to explore the effect of glutaminolysis inhibition on endometrial fibrosis.

Results: We found that GLS1 expression was significantly increased in activated ESCs models and fibrotic endometrium. Glutaminolysis inhibition by GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES or glutamine deprivation treatment suppressed the expression of two fibrotic markers, α-SMA and collagen I, as well as the mitochondrial function and mTORC1 signaling in ESCs. Furthermore, inhibition of the mTORC1 signaling pathway by rapamycin suppressed ESCs activation. In IUA mice models, BPTES treatment significantly ameliorated endometrial fibrosis and improved pregnancy outcomes.

Conclusion: Glutaminolysis and glutaminolysis-associated mTOR signaling play a role in the activation of ESCs and the pathogenesis of endometrial fibrosis through regulating mitochondrial function. Glutaminolysis inhibition suppresses the activation of ESCs, which might be a novel therapeutic strategy for IUA.

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谷氨酰胺溶解通过调节线粒体功能调节宫腔内粘连的子宫内膜纤维化。
背景:子宫内膜纤维化是宫腔内粘连(IUA)的一个重要特征,是由子宫内膜基质细胞(ESC)过度分化和活化引起的。谷氨酰胺分解是谷氨酰胺(Gln)的代谢过程,与多种类型的器官纤维化有关。迄今为止,人们对谷氨酰胺溶解是否在子宫内膜纤维化中发挥作用知之甚少:方法:利用 TGF-β1 建立了 ESCs 活化模型,然后进行 RNA 序列分析。实验验证了活化的 ESCs 中谷氨酰胺酶 1(GLS1)在 RNA 和蛋白质水平上的表达变化。收集人类 IUA 样本以验证 GLS1 在子宫内膜纤维化中的表达。将 GLS1 抑制剂和谷氨酰胺剥夺应用于 ESCs 模型,研究谷氨酰胺溶解在 ESCs 活化过程中的生物学功能和机制。建立IUA小鼠模型,探讨谷氨酰胺酵解抑制对子宫内膜纤维化的影响:结果:我们发现,GLS1在活化的ESCs模型和纤维化的子宫内膜中表达明显增加。通过GLS1抑制剂双-2-(5-苯乙酰氨基-1,2,4-噻二唑-2-基)乙基硫醚(BPTES)抑制谷氨酰胺分解或谷氨酰胺剥夺处理,可抑制两种纤维化标志物α-SMA和胶原蛋白I的表达,并抑制ESCs的线粒体功能和mTORC1信号传导。此外,雷帕霉素抑制了 mTORC1 信号通路,从而抑制了 ESCs 的活化。在IUA小鼠模型中,BPTES治疗能明显改善子宫内膜纤维化并改善妊娠结局:结论:谷氨酰胺酵解和谷氨酰胺酵解相关的mTOR信号转导通过调节线粒体功能在激活ESCs和子宫内膜纤维化的发病机制中发挥作用。抑制谷氨酰胺酵解可抑制 ESCs 的活化,这可能是 IUA 的一种新型治疗策略。
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来源期刊
Biological Research
Biological Research 生物-生物学
CiteScore
10.10
自引率
0.00%
发文量
33
审稿时长
>12 weeks
期刊介绍: Biological Research is an open access, peer-reviewed journal that encompasses diverse fields of experimental biology, such as biochemistry, bioinformatics, biotechnology, cell biology, cancer, chemical biology, developmental biology, evolutionary biology, genetics, genomics, immunology, marine biology, microbiology, molecular biology, neuroscience, plant biology, physiology, stem cell research, structural biology and systems biology.
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