Poldip2通过AMPK/ULK1/Pink1通路损害线粒体自噬，从而加重糖尿病视网膜病变的炎症

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-05-02 DOI:10.1016/j.lfs.2025.123681

Siyu Lin , Zhiyu Ji , Jie Gao , Jiawei Fan , Jingjing Hou , Sha Liu , Chuanxi Wang , Keyang Chen , Liming Tao , Zhengxuan Jiang

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引用次数: 0

摘要

背景和目的炎症是糖尿病视网膜病变（DR）病理生理学的一个重要方面。聚合酶δ相互作用蛋白2 （Poldip2）与多种疾病中的炎症有关，但其在DR中的作用尚不清楚。方法透射电镜（TEM）显示，链脲佐菌素（STZ）诱导的糖尿病大鼠视网膜中受损线粒体的积累导致了明显的线粒体自噬减少。体内给予stz诱导的DR大鼠AAV9-Poldip2-shRNA，部分恢复线粒体自噬。在高糖（HG）条件下培养的小胶质细胞（BV2）也表现出类似的行为。同样，BV2接受Poldip2- sirna处理，进一步探索Poldip2的调控机制。结果在体内，Poldip2与VEGFR和SQSTM1/P62一起显著升高，而线粒体自噬标志物被抑制。在HG条件下，BV2分泌大量促炎因子。这些hg培养的BV2显著影响人视网膜微血管内皮细胞（HRMECs），导致血管生成。值得注意的是，敲低Poldip2可通过阻止其泛素化介导的降解，从而显著增加Pink1，从而增强线粒体自噬，减少视网膜炎症。结论Poldip2通过促进Pink1降解，抑制有丝分裂，导致炎症，从而参与DR的发生。靶向Poldip2可能为DR提供新的治疗策略。

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Poldip2 Aggravates inflammation in diabetic retinopathy by impairing mitophagy via the AMPK/ULK1/Pink1 pathway

Background and aim

Inflammation is a crucial aspect of the pathophysiology of diabetic retinopathy (DR). Polymerase delta-interacting protein 2 (Poldip2) has been linked to inflammation in various disorders, but its role in DR remains unclear. This study aims to elucidate the underlying mechanisms of Poldip2 in DR.

Methods

Transmission Electron Microscopy (TEM) revealed significant mitophagy reduction due to the accumulation of damaged mitochondria in the retinas of Streptozotocin (STZ)-induced diabetic Sprague Dawley (SD) rats. In vivo, AAV9-Poldip2-shRNA was administered to STZ-induced DR rats, partially restoring mitophagy. Microglia (BV2) cells cultured in high glucose (HG) conditions exhibited similar behavior. Likewise, BV2 received Poldip2-siRNA treatment to further explore the regulatory mechanism of Poldip2.

Results

In vivo, Poldip2 was significantly elevated alongside VEGFR and SQSTM1/P62, while mitophagy markers were inhibited. Under HG conditions, BV2 secret large amounts of pro-inflammatory factors. Human Retinal Microvascular Endothelial Cells (HRMECs) were significantly affected by these HG-cultured BV2, leading to angiogenesis. Notably, Poldip2 knockdown significantly increased Pink1 by preventing its ubiquitination-mediated degradation, thereby enhancing mitophagy and reducing retinal inflammation.

Conclusion

Our findings suggest that Poldip2 contributes to DR by promoting Pink1 degradation, which inhibits mitophagy and leads to inflammation. Targeting Poldip2 may offer a novel therapeutic strategy for DR.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.