Dysregulated metabolic pathways in age-related macular degeneration
Dysregulated metabolic pathways in age-related macular degeneration
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DOI：
10.1038/s41598-020-59244-4
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发表时间：
2020-02-12
影响因子：
4.6
通讯作者：
Golestaneh, Nady
中科院分区：
文献类型：
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作者：
Zhang, Meng;Jiang, Nisi;Golestaneh, Nady
视网膜相关性黄斑变性是西方世界55岁及以上人群视力受损的主要原因。最近，我们已经表明自噬在AMD供体眼睛（AMD RPE）的视网膜色素上皮（RPE）中是功能障碍的。我们还发现AMD RPE中活性氧（ROS）产生增加，细胞质糖原积累增加，线粒体功能障碍和解体，以及LAMP-1阳性细胞器扩大和环状。然而，诱导这些异常的潜在机制仍有待阐明。在这里，通过进行全面的研究，我们发现与正常RPE相比，AMD RPE中PAPR 2表达增加，NAD+和SIRT 1减少，PGC-1 α乙酰化增加（非活性形式），AMPK活性降低，mTOR通路过度活跃。代谢组学和脂质组学揭示了与正常RPE相比AMD RPE中失调的代谢物，包括甘油磷脂代谢，其涉及自噬、脂质和蛋白质代谢、谷胱甘肽、鸟苷和L-谷氨酸，其涉及对氧化应激和神经毒性的保护，进一步支持了我们的观察结果。我们的数据显示代谢途径失调是AMD病理生理学的重要贡献者，并促进了这种视觉系统衰弱疾病的新治疗策略的发展。
Age-related macular degeneration is a major cause of vision impairment in the Western world among people of 55 years and older. Recently we have shown that autophagy is dysfunctional in the retinal pigment epithelium (RPE) of the AMD donor eyes (AMD RPE). We also showed increased reactive oxygen (ROS) production, increased cytoplasmic glycogen accumulation, mitochondrial dysfunction and disintegration, and enlarged and annular LAMP-1-positive organelles in AMD RPE. However, the underlying mechanisms inducing these abnormalities remain to be elucidated. Here, by performing a comprehensive study, we show increased PAPR2 expression, deceased NAD+, and SIRT1, increased PGC-1 alpha acetylation (inactive form), lower AMPK activity, and overactive mTOR pathway in AMD RPE as compared to normal RPE. Metabolomics and lipidomics revealed dysregulated metabolites in AMD RPE as compared to normal RPE, including glycerophospholipid metabolism, involved in autophagy, lipid, and protein metabolisms, glutathione, guanosine, and L-glutamic acid, which are implicated in protection against oxidative stress and neurotoxicity, further supporting our observations. Our data show dysregulated metabolic pathways as important contributors to AMD pathophysiology, and facilitate the development of new treatment strategies for this debilitating disease of the visual system.