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GPCR拮抗剂药物CM-20可刺激人视网膜色素上皮细胞的线粒体活性。

The GPCR Antagonistic Drug CM-20 Stimulates Mitochondrial Activity in Human RPE Cells.

作者信息

Chang Qing, Chen Siquan, Yang Tahua

机构信息

University of Illinois Technology Innovation Lab and Argos Vision Inc., Chicago, United States.

Cellular Screening Center, The University of Chicago, Chicago, United States.

出版信息

Open Biochem J. 2022;16. doi: 10.2174/1874091X-v16-e2206270. Epub 2022 Aug 22.

DOI:10.2174/1874091X-v16-e2206270
PMID:36090845
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9460984/
Abstract

BACKGROUND

Mitochondrial dysfunction in retinal pigment epithelium (RPE) is a pathogenic factor in age-related macular degeneration (AMD). Improvement of mitochondrial function may ameliorate RPE bioenergetics status, which may in turn nourish the retinal photoreceptors against degenerative loss.

OBJECTIVE

The purpose of this study is to examine the G-protein coupled receptor (GPCR) antagonistic drug CM-20 in modulating mitochondrial function in RPE cells.

METHODS

Human-derived ARPE-19 cell line was differentiated to improve RPE morphology. Dose response of CM-20 was performed to examine mitochondrial membrane potential (MMP). Secondary validation with multiplexed live-cell mitochondrial imaging was performed. Protection of CM-20 to mitochondria against oxidative stress was detected under co-treatment with hydrogen peroxide.

RESULTS

Treatment with CM-20 elicited a dose-dependent increase of MMP. Multiplexed live-cell mitochondrial imaging showed consistent increase of MMP at an optimal concentration of CM-20 (12.5 μM). MMP was significantly reduced under hydrogen peroxide-induced oxidative stress and treatment with CM-20 showed rescue effects to MMP.

CONCLUSION

CM-20 increases mitochondrial function and protects mitochondria under oxidative stress. As both GPCRs and mitochondria are potential drug targets, retinal neuroprotective testing of CM-20 is warranted in animal models of retinal degeneration.

摘要

背景

视网膜色素上皮（RPE）中的线粒体功能障碍是年龄相关性黄斑变性（AMD）的致病因素。改善线粒体功能可能会改善RPE的生物能量状态，进而滋养视网膜光感受器以防止退化性损失。

目的

本研究旨在检测G蛋白偶联受体（GPCR）拮抗剂CM-20对RPE细胞线粒体功能的调节作用。

方法

对人源ARPE-19细胞系进行分化以改善RPE形态。进行CM-20的剂量反应以检测线粒体膜电位（MMP）。采用多重活细胞线粒体成像进行二次验证。在与过氧化氢共同处理下，检测CM-20对线粒体抗氧化应激的保护作用。

结果

CM-20处理引起MMP呈剂量依赖性增加。多重活细胞线粒体成像显示，在CM-20的最佳浓度（12.5μM）下，MMP持续增加。在过氧化氢诱导的氧化应激下，MMP显著降低，而CM-20处理对MMP有挽救作用。

结论

CM-20可增加线粒体功能并在氧化应激下保护线粒体。由于GPCR和线粒体都是潜在的药物靶点，因此有必要在视网膜变性动物模型中对CM-20进行视网膜神经保护测试。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/03e6b1cb2fb2/nihms-1834511-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/945226c91b31/nihms-1834511-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/35f495afbb68/nihms-1834511-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/9594d8f1cf00/nihms-1834511-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/6ec72a8038c8/nihms-1834511-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/03e6b1cb2fb2/nihms-1834511-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/945226c91b31/nihms-1834511-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/35f495afbb68/nihms-1834511-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/9594d8f1cf00/nihms-1834511-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/6ec72a8038c8/nihms-1834511-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89c2/9460984/03e6b1cb2fb2/nihms-1834511-f0005.jpg

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