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

Authors

Miret-Casals, Laia; Sebasti?n, David; Brea, Jos?; Rico-Leo, Eva M; Palac?n, Manuel; Fern?ndez-Salguero, Pedro M; Loza, M Isabel; Albericio, Fernando; Zorzano, Antonio

Publication Year 1905
Journal Cell Chemical Biology
Chapter
Pages 268-278.e4
Volume 25
Issue 3
Issn
Isbn
PMID 29290623.0
PMCID
DOI 10.1016/j.chembiol.2017.12.001
URL http://dx.doi.org/10.1016/j.chembiol.2017.12.001

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. Copyright ? 2017 Elsevier Ltd. All rights reserved.