Mitochondria are dynamic organelles that produce most of the cellular ATP, and are involved in many other cellular functions such as Ca2+signaling, differentiation, apoptosis, cell cycle, and cell growth. One key process of mitochondrial dynamics is mitochondrial fusion, which is catalyzed by mitofusins (MFN1 and MFN2) and OPA1. The outer mitochondrial membrane protein MFN2 plays a relevant role in the maintenance of mitochondrial metabolism, insulin signaling, and mutations that cause neurodegenerative disorders. Therefore, modulation of proteins involved in mitochondrial dynamics has emerged as a potential pharmacological strategy. Here, we report the identification of small molecules by high-throughput screen that promote mitochondrial elongation in an MFN1/MFN2-dependent manner. Detailed analysis of their mode of action reveals a previously unknown connection between pyrimidine metabolism and mitochondrial dynamics. Our data indicate a link between pyrimidine biosynthesis and mitochondrial dynamics, which maintains cell survival under stress conditions characterized by loss of pyrimidine synthesis.

中文翻译：

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线粒体融合新激活剂的鉴定揭示了线粒体形态与嘧啶代谢之间的联系

线粒体是产生大多数细胞ATP的动态细胞器，并参与许多其他细胞功能，例如Ca2 +信号传导，分化，凋亡，细胞周期和细胞生长。线粒体动力学的一个关键过程是线粒体融合，它是由线粒体融合素（MFN1和MFN2）和OPA1催化的。线粒体外膜蛋白MFN2在维持线粒体代谢，胰岛素信号传导和引起神经退行性疾病的突变中起着重要作用。因此，涉及线粒体动力学的蛋白质调节已成为一种潜在的药理策略。在这里，我们报告通过高通量筛选以MFN1 / MFN2依赖性方式促进线粒体伸长的小分子鉴定。他们的作用方式的详细分析揭示了嘧啶代谢和线粒体动力学之间以前未知的联系。我们的数据表明嘧啶生物合成与线粒体动力学之间存在联系，该联系在以嘧啶合成为特征的应激条件下维持细胞存活。