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Article Dans Une Revue Molecular Cell Année : 2018

Mitochondrial MDM2 regulates respiratory complex i activity independently of p53

Béatrice Chabi
François Casas
Anne Lombes
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-01837662 , version 1 (12-07-2018)

Identifiants

Citer

Giuseppe Arena, Madi Yann Cisse, Samuel Pyrdziak, Laurent Chatre, Romain Riscal, et al.. Mitochondrial MDM2 regulates respiratory complex i activity independently of p53. Molecular Cell, 2018, 69 (4), pp.594-609. ⟨10.1016/j.molcel.2018.01.023⟩. ⟨hal-01837662⟩
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