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Mitochondrial MDM2 regulates respiratory complex i activity independently of p53

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Arena, Giuseppe | Cisse, 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, Béatrice | Koechlin Ramonatxo, Christelle | Orsetti, Beatrice | Vincent, Charles | Casas, François | Marine, Jean-Christophe | Etienne-Manneville, Sandrine | Bernex, Florence | Lombes, Anne | Cameron, Craig Eugene | Dubouchaud, Herve | Ricchetti, Miria | Linares, Laetitia Karine | Le Cam, Laurent

Edité par CCSD ; Cell Press -

International audience. 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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