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小分子对线粒体-内质网接触（MERCs）的调节作为恢复肌萎缩侧索硬化模型中脂质代谢的新策略

Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model.

作者信息

Etxebeste-Mitxeltorena Mikel, Flores-Romero Hector, Ramos-Inza Sandra, Masiá Esther, Nenchova Maria, Montesinos Jorge, Martinez-Gonzalez Loreto, Porras Gracia, Orzáez Mar, Vicent María J, Gil Carmen, Area-Gomez Estela, Garcia-Saez Ana J, Martinez Ana

机构信息

Centro de Investigaciones Biológicas "Margarita Salas"-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.

Institute for Genetics, CECAD, University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.

出版信息

J Med Chem. 2025 Jan 23;68(2):1179-1194. doi: 10.1021/acs.jmedchem.4c01368. Epub 2025 Jan 8.

DOI:10.1021/acs.jmedchem.4c01368
PMID:39778888
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11770630/
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control. Using the MERLIN biosensor in a high-throughput screening within the EU-OPENSCREEN ERIC, we discovered small molecules that increase MERCs in HCT116 cells, enhancing their ability to uptake cholesterol. We demonstrated that cholesterol trafficking is decreased in an ALS patient-derived cell model, and this trafficking is restored after treatment with the discovered MERC modulator . Electron microscopy revealed that treatment with compound increases MERCs, promotes lipid droplet formation, and restores mitochondrial cristae. Overall, the brain-permeable MERC modulator, compound , may serve as a valuable pharmacological tool for studying MAM function and holds potential for in vivo studies in ALS and other MAM dysfunction diseases.

摘要

肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，尚无有效治疗方法。ALS中运动神经元的进行性死亡与脂质代谢改变有关。由于其调节发生在线粒体相关内质网（ER）膜（MAMs）中，线粒体-内质网接触（MERCs）的调节正成为MAM形成和脂质代谢控制的关键因素。在欧盟开放筛选平台ERIC的高通量筛选中使用MERLIN生物传感器，我们发现了能增加HCT116细胞中MERCs的小分子，增强了它们摄取胆固醇的能力。我们证明，在ALS患者来源的细胞模型中胆固醇转运减少，而用发现的MERC调节剂处理后这种转运得以恢复。电子显微镜显示，化合物处理可增加MERCs，促进脂滴形成，并恢复线粒体嵴。总体而言，具有脑渗透性的MERC调节剂化合物可能是研究MAM功能的有价值的药理学工具，在ALS和其他MAM功能障碍疾病的体内研究中具有潜力。

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Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis.肌萎缩侧索硬化症的分子病理学、诊断和治疗进展。
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