Mitochondrial MDM2 regulates respiratory complex i activity independently of p53
Journal article
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, ... Le Cam, Laurent. (2018). Mitochondrial MDM2 regulates respiratory complex i activity independently of p53. Molecular Cell. 69(4), pp. 594 - 609. https://doi.org/10.1016/j.molcel.2018.01.023
Authors | 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 and Le Cam, Laurent |
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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. |
Year | 2018 |
Journal | Molecular Cell |
Journal citation | 69 (4), pp. 594 - 609 |
Publisher | Cell Press |
ISSN | 1097-2765 |
Digital Object Identifier (DOI) | https://doi.org/10.1016/j.molcel.2018.01.023 |
Scopus EID | 2-s2.0-85042135530 |
Page range | 594 - 609 |
Research Group | Mary MacKillop Institute for Health Research |
Publisher's version | File Access Level Controlled |
Place of publication | United States of America |
https://acuresearchbank.acu.edu.au/item/889w8/mitochondrial-mdm2-regulates-respiratory-complex-i-activity-independently-of-p53
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