Identification of New Activators of Mitochondrial Fusion Reveals a Link between Mitochondrial Morphology and Pyrimidine Metabolism

Mitochondria are dynamic organelles that produce most of the cellular ATP, and are involved in many other cellular functions such as Ca 2+ 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. Miret-Casals et al. identify leflunomide as an activator of MFN1/2 expression and demonstrate a connection between pyrimidine metabolism and mitochondrial fusion. This connection provides new avenues toward the treatment of diseases linked to mitochondrial dysfunction.