SHMT2 overexpression improves glaucoma by enhancing mitophagy in retinal ganglion cells through promoting the phospho of PINK1.

IF 2.4 3区医学 Q2 PATHOLOGY

Diagnostic Pathology Pub Date : 2025-07-02 DOI:10.1186/s13000-025-01675-6

Liying Cui, Baojun Wang

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引用次数: 0

Abstract

Background: Glaucoma is a major eye disease that causes blindness. The loss of retinal ganglion cells (RGCs) due to mitophagy impairment is a key driver of glaucoma. SHMT2 depletion leads to an increase in reactive oxygen species (ROS), but its role in regulating mitophagy remains unclear. This study aims to investigate the mechanism by which SHMT2 contributes to glaucoma through the regulation of RGC mitophagy.

Methods: The role of SHMT2 in glaucoma was evaluated through hematoxylin and eosin (H&E) staining and immunofluorescence (IF) staining of acute ocular hypertension (AOH) mouse eyeballs. Mitophagy was assessed by measuring LDH release, apoptosis, mitochondrial membrane potential, lipid ROS, and the protein levels of mitophagy-related proteins in RGCs. The underlying mechanism was investigated using co-immunoprecipitation, IF staining, and Western blot analysis.

Results: Results showed that SHMT2 expression was decreased in the AOH mouse model. NMDA inhibited mitophagy in RGCs, which was restored by SHMT2 overexpression. Moreover, SHMT2 overexpression stabilized PINK1 expression by enhancing the phosphorylation of PINK1. In vivo experiments suggested that SHMT2 overexpression increased the thickness of the retinal ganglion cell-inner plexiform layer.

Conclusion: This study confirmed that SHMT2 overexpression alleviated glaucoma by enhancing mitophagy in RGCs through the upregulation of PINK1 phosphorylation, suggesting that SHMT2 may serve as a potential therapeutic target for glaucoma.

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SHMT2过表达通过促进PINK1磷酸化，增强视网膜神经节细胞的线粒体自噬，从而改善青光眼。

背景：青光眼是导致失明的主要眼病。由于线粒体自噬损伤导致的视网膜神经节细胞（RGCs）的丢失是青光眼的关键驱动因素。SHMT2耗竭导致活性氧（ROS）增加，但其在调节线粒体自噬中的作用尚不清楚。本研究旨在探讨SHMT2通过调控RGC自噬参与青光眼的机制。方法：采用苏木精伊红（H&E）染色和免疫荧光（IF）染色观察急性高眼压（AOH）小鼠眼球，评价SHMT2在青光眼中的作用。通过测量RGCs中LDH释放、凋亡、线粒体膜电位、脂质ROS和线粒体自噬相关蛋白的蛋白水平来评估线粒体自噬。使用免疫共沉淀、IF染色和Western blot分析研究其潜在机制。结果：结果显示在AOH小鼠模型中SHMT2表达降低。NMDA抑制RGCs的线粒体自噬，并通过过表达SHMT2恢复线粒体自噬。此外，SHMT2过表达通过增强PINK1的磷酸化来稳定PINK1的表达。体内实验表明，SHMT2过表达增加了视网膜神经节细胞内丛状层的厚度。结论：本研究证实SHMT2过表达通过上调PINK1磷酸化，增强RGCs的自噬从而减轻青光眼，提示SHMT2可能是青光眼的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diagnostic Pathology 医学-病理学

CiteScore

4.60

自引率

0.00%

发文量

审稿时长

1 months

期刊介绍： Diagnostic Pathology is an open access, peer-reviewed, online journal that considers research in surgical and clinical pathology, immunology, and biology, with a special focus on cutting-edge approaches in diagnostic pathology and tissue-based therapy. The journal covers all aspects of surgical pathology, including classic diagnostic pathology, prognosis-related diagnosis (tumor stages, prognosis markers, such as MIB-percentage, hormone receptors, etc.), and therapy-related findings. The journal also focuses on the technological aspects of pathology, including molecular biology techniques, morphometry aspects (stereology, DNA analysis, syntactic structure analysis), communication aspects (telecommunication, virtual microscopy, virtual pathology institutions, etc.), and electronic education and quality assurance (for example interactive publication, on-line references with automated updating, etc.).