Journal
MOLECULAR CELL
Volume 69, Issue 4, Pages 594-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.01.023
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Funding
- Ligue contre le Cancer (Equipe labelisee)
- French National Health Institute for Biomedical Research (INSERM)
- French National Cancer Institute (INCa)
- General Direction for Care Provision [INCa-DGOS-Inserm 6045]
- Laboratory of Excellence EpiGenMed [ANR-10-LABX-12-01]
- Region Languedoc Roussillon
- University of Montpellier
- Fondation de France
- Association pour la Recherche contre le Cancer (ARC)
- French Ministry for Education and Research
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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.
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