Article (Scientific journals)
Mitochondrial MDM2 Regulates Respiratory Complex I Activity Independently of p53.
Arena, Giuseppe; Cissé, Madi Yann; Pyrdziak, Samuel et al.
2018In Molecular Cell, 69 (4), p. 594-609.e8
Peer Reviewed verified by ORBi


Full Text
Arena et al., 2018 - Mol Cell.pdf
Publisher postprint (4.51 MB)

All documents in ORBilu are protected by a user license.

Send to


Keywords :
Adenocarcinoma/genetics/metabolism/pathology; Animals; Carcinoma, Non-Small-Cell Lung/genetics/metabolism/pathology; Cell Movement; Cell Transformation, Neoplastic/genetics/metabolism/pathology; Electron Transport Complex I/genetics/metabolism; Gene Expression Regulation, Neoplastic; Genome, Mitochondrial; Humans; Lung Neoplasms/genetics/metabolism/pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria/genetics/metabolism/pathology; Neoplasm Invasiveness; Oxidative Stress; Proto-Oncogene Proteins c-mdm2/genetics/metabolism; Signal Transduction; Transcription, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p53/genetics/metabolism; Xenograft Model Antitumor Assays; MDM2; MT-ND6; hypoxia; migration; mitochondria; respiratory complex I
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Arena, Giuseppe ;  IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier F-34298, France
Cissé, Madi Yann
Pyrdziak, Samuel
Chatre, Laurent
Riscal, Romain
Fuentes, Maryse
Arnold, Jamie Jon
Kastner, Markus
Gayte, Laurie
Bertrand-Gaday, Christelle
Nay, Kevin
Angebault-Prouteau, Claire
Murray, Kerren
Chabi, Beatrice
Koechlin-Ramonatxo, Christelle
Orsetti, Béatrice
Vincent, Charles
Casas, François
Marine, Jean-Christophe
Etienne-Manneville, Sandrine
Bernex, Florence
Lombès, Anne
Cameron, Craig Eugene
Dubouchaud, Hervé
Ricchetti, Miria
Linares, Laetitia Karine
Le Cam, Laurent
More authors (17 more) Less
External co-authors :
Language :
Title :
Mitochondrial MDM2 Regulates Respiratory Complex I Activity Independently of p53.
Publication date :
Journal title :
Molecular Cell
Publisher :
Cell Press, United States - Massachusetts
Volume :
Issue :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright © 2018 Elsevier Inc. All rights reserved.
Available on ORBilu :
since 05 April 2023


Number of views
17 (0 by Unilu)
Number of downloads
5 (0 by Unilu)

WoS citations


Similar publications

Contact ORBilu