Mitochondrial MDM2 Regulates Respiratory Complex I Activity Independently of p53

Giuseppe Arena, Madi Yann Cissé, Samuel Pyrdziak, Laurent Chatre, Romain Riscal, Maryse Fuentes, Jamie Jon Arnold, Markus Kastner, Laurie Gayte, Christelle Bertrand-Gaday, Kevin Nay, Claire Angebault-Prouteau, Kerren Murray, Beatrice Chabi, Christelle Koechlin-Ramonatxo, Béatrice Orsetti, Charles Vincent, François Casas, Jean Christophe Marine, Sandrine Etienne-MannevilleFlorence Bernex, Anne Lombès, Craig Eugene Cameron, Hervé Dubouchaud, Miria Ricchetti, Laetitia Karine Linares, Laurent Le Cam

Research output: Contribution to journalArticle

18 Scopus citations

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. Arena et al. show that the proto-oncogene MDM2 is recruited to mitochondria independently of its well-known partner p53. By repressing transcription of a specific subunit of the electron transport chain encoded by the mitochondrial genome, mitochondrial MDM2 controls respiration, influencing skeletal muscle function and cancer cell migration.

Original languageEnglish (US)
Pages (from-to)594-609.e8
JournalMolecular cell
Volume69
Issue number4
DOIs
StatePublished - Feb 15 2018

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Arena, G., Cissé, M. Y., Pyrdziak, S., Chatre, L., Riscal, R., Fuentes, M., Arnold, J. J., Kastner, M., Gayte, L., Bertrand-Gaday, C., Nay, K., Angebault-Prouteau, C., Murray, K., Chabi, B., Koechlin-Ramonatxo, C., Orsetti, B., Vincent, C., Casas, F., Marine, J. C., ... Le Cam, L. (2018). Mitochondrial MDM2 Regulates Respiratory Complex I Activity Independently of p53. Molecular cell, 69(4), 594-609.e8. https://doi.org/10.1016/j.molcel.2018.01.023