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

Abstract

Mitochondria are dynamic organelles that produce most of the cellular ATP, and are involved in many other cellular functions such as Ca 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.

Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer

“…Leflunomide activates MFN2 expression and improves survival in multiple mouse models of pancreatic cancer. Recently, the FDA-approved anti-arthritis drug, leflunomide, was found to also enhance the expression of MFN2 and promote mitochondrial fusion in HeLa cells (13). To determine whether leflunomide had similar activity in pancreatic cancer, we treated KPC cells with the drug and observed a 2-fold enhancement of Mfn2 mRNA ( Figure 4A) and MFN2 protein levels ( Figure 4B).…”

Comparison between wild and related cultivated rice species reveals strong impacts of crop domestication on methane metabolism of the rhizomicrobiome

“…Both in African and Asian wild rice the interactive networks were more complex than in the related cultivated rice. The methane metabolism related KOs of wild rice were mainly affected by functional KOs belonging to carbon xation pathway, pyruvate metabolism, glycolysis/gluconeogenesis and pyrimidine metabolism which can provide energy sources and intermediates for methane metabolism [39][40][41]. The methane metabolisms related KO of cultivated rice were mainly affected by functional KOs belonging to phentlalanine, tyrosine and tryptophan biosynthesis as well as retinol metabolism.…”

Mitochondrial Fusion Suppresses Pancreatic Cancer Growth via Reduced Oxidative Metabolism

“…We would predict that the induction of mitochondrial fusion may be highly effective without causing the excessive toxicity that a general mitochondrial inhibitor might have. Future studies should be devoted to finding other small molecules that could induce fusion in other methods (Miret-Casals et al, 2017), which could be tested in clinical trials.…”