子宫内膜异位症患者因LDHA m6A甲基化导致糖酵解减少,损害其去个体化并导致相关不孕。

IF 3.6 2区 医学 Q1 PATHOLOGY
Ruiweng Weng, Yi Liu, Wenqian Xiong
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引用次数: 0

摘要

子宫内膜异位症相关的不孕症是一个普遍的生殖健康问题的全球意义。子宫内膜功能异常越来越被认为是影响个体不孕的关键因素。在本研究中,从子宫内膜异位症患者获得的分泌期子宫内膜组织中观察到糖酵解活性显著降低,这种代谢缺陷归因于乳酸脱氢酶a (LDHA)表达下调。在小鼠模型中发现,糖酵解受损可诱导子宫内膜脱个体化缺陷,并导致子宫内膜异位症相关不孕。从机制上说,抑制LDHA促进了活性氧(ROS)的产生和子宫内膜基质细胞的凋亡,最终导致基质细胞脱胞化受损。此外,在子宫内膜异位症患者的异位子宫内膜中证实LDHA表达降低,这与n6 -甲基腺苷(m6A)去甲基化活性降低有关。这种m6A去甲基化的衰减反过来归因于alkB同源物5 (ALKBH5)的表达下调,ALKBH5是负责m6A去甲基化修饰的关键酶。总之,我们的研究结果表明,子宫内膜异位症患者异位子宫内膜中m6A甲基化水平升高会损害子宫内膜糖酵解代谢和子宫内膜间质细胞的脱个体化,从而导致子宫内膜异位症相关不孕。这种病理级联是由LDHA表达下调介导的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Decreased Glycolysis due to LDHA m6A methylation in Endometrium of endometriosis impairs its decidualization and contributes to related infertility.

Endometriosis-related infertility is a prevalent reproductive health concern of global significance. Functional abnormalities of the endometrium are increasingly recognized as a pivotal contributor to infertility in affected individuals. In the present study, a significant reduction in glycolytic activity was observed in secretory-phase endometrial tissues obtained from patients with endometriosis, and this metabolic defect was attributed to downregulated expression of lactate dehydrogenase A (LDHA). This impaired glycolysis was found to induce defective endometrial decidualization and contribute to endometriosis-related infertility in a mouse model. Mechanistically, inhibition of LDHA promoted the production of reactive oxygen species (ROS) and apoptosis of endometrial stromal cells, ultimately resulting in compromised stromal cell decidualization. Furthermore, reduced LDHA expression was confirmed in the eutopic endometrium of patients with endometriosis, which was associated with decreased N6-methyladenosine (m6A) demethylation activity. This attenuation of m6A demethylation was, in turn, attributed to the downregulated expression of alkB homolog 5 (ALKBH5)-a key enzyme responsible for m6A demethylation modification. Collectively, our findings demonstrate that elevated m6A methylation levels in the eutopic endometrium of patients with endometriosis impair endometrial glycolytic metabolism and decidualization of endometrial stromal cells, thereby contributing to endometriosis-related infertility. This pathological cascade is mediated by the downregulation of LDHA expression.

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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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