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Mitochondrial MDM2 regulates respiratory complex i activity independently of p53
Arena, Giuseppe Cissé, Madi Yann Pyrdziak, Samuel Chatre, Laurent Riscal, Romain Fuentes, Maryse Arnold, Jamie Jon Kastner, Markus Gayte, Laurie Bertrand-Gaday, Christelle
Arena, Giuseppe
Cissé, Madi Yann
Pyrdziak, Samuel
Chatre, Laurent
Riscal, Romain
Fuentes, Maryse
Arnold, Jamie Jon
Kastner, Markus
Gayte, Laurie
Bertrand-Gaday, Christelle
Author
Arena, Giuseppe
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
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
Abstract
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.
Keywords
Date
2018
Type
Journal article
Journal
Molecular Cell
Book
Volume
69
Issue
4
Page Range
594-609
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
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Relation URI
Source URL
Event URL
Open Access Status
License
File Access
Controlled