Mitochondria are subcellular organelles that perform a variety of critical biological functions, including ATP production and acting as hubs of immune and apoptotic signalling. Mitochondrial dysfunction has been extensively linked to the pathology of multiple neurodegenerative disorders, resulting in significant investment from the drug discovery community. Despite extensive efforts, there remains no disease modifying therapies for neurodegenerative disorders. This manuscript aims to review the compounds historically used to modulate the mitochondrial network through the lens of modern medicinal chemistry, and to offer a perspective on the evidence that relevant exposure was achieved in a representative model and that exposure was likely to result in target binding and engagement of pharmacology. We hope this manuscript will aid the community in identifying those targets and mechanisms which have been convincingly (in)validated with high quality chemical matter, and those for which an opportunity exists to explore in greater depth.

中文翻译：

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线粒体功能障碍的药物化学：调节线粒体健康努力的重要概述

线粒体是亚细胞细胞器，具有多种重要的生物学功能，包括产生 ATP 以及充当免疫和细胞凋亡信号传导的中枢。线粒体功能障碍与多种神经退行性疾病的病理学密切相关，导致药物发现界的大量投资。尽管付出了广泛的努力，但仍然没有针对神经退行性疾病的疾病修饰疗法。本手稿旨在通过现代药物化学的视角回顾历史上用于调节线粒体网络的化合物，并提供证据的观点，即在代表性模型中实现了相关暴露，并且暴露可能导致目标结合和药理学的参与。我们希望这份手稿将帮助社区确定那些已经通过高质量化学物质令人信服地验证的目标和机制，以及那些有机会更深入探索的目标和机制。