Author: Arena, G.; Cisse, M.Y.; Pyrdziak, S.; Chatre, L.; Riscal, R.; Fuentes, M.; Arnold, J.J.; Kastner, M.; Gayte, L.; Bertrand-Gaday, C.; Nay, K.; Angebault-Prouteau, C.; Murray, K.; Chabi, B.; Koechlin-Ramonatxo, C.; Orsetti, B.; Vincent, C.; Casas, F.; Marine, J.-C.; Etienne-Manneville, S.; Bernex, F.; Lombes, A.; Cameron, C.E.; Dubouchaud, H.; Ricchetti, M.; Linares, L.K.; Le Cam, L.
Description: Accumulating evidence indicates that the MDM2 oncoprotein promotes tumorigenesis beyond its canonical negative effects on the p53 tumor suppressor, but these p53-independent functions remain poorly understood. Here, we show that a fraction of endogenous MDM2 is actively imported in mitochondria to control respiration and mitochondrial dynamics independently of p53. Mitochondrial MDM2 represses the transcription of NADH-dehydrogenase 6 (MT-ND6) in vitro and in vivo, impinging on respiratory complex I activity and enhancing mitochondrial ROS production. Recruitment of MDM2 to mitochondria increases during oxidative stress and hypoxia. Accordingly, mice lacking MDM2 in skeletal muscles exhibit higher MT-ND6 levels, enhanced complex I activity, and increased muscular endurance in mild hypoxic conditions. Furthermore, increased mitochondrial MDM2 levels enhance the migratory and invasive properties of cancer cells. Collectively, these data uncover a previously unsuspected function of the MDM2 oncoprotein in mitochondria that play critical roles in skeletal muscle physiology and may contribute to tumor progression.
Subject Headings: MDM2; Mt-Nd6; Hypoxia; Migration; Mitochondria; Respiratory complex I; p53; Cancer
Publication year: 2018
Journal or book title: Molecular Cell
Volume: 69
Issue: 4
Pages: 594-609.e8
Find the full text : https://www.sciencedirect.com/science/article/pii/S1097276518300522
Find more like this one (cited by): https://scholar.google.com/scholar?cites=17835177264043819980&as_sdt=1000005&sciodt=0,16&hl=en
Type: Journal Article
Serial number: 2278