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
AuthorsArena, 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
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.

Year2018
JournalMolecular Cell
Journal citation69 (4), pp. 594 - 609
PublisherCell Press
ISSN1097-2765
Digital Object Identifier (DOI)https://doi.org/10.1016/j.molcel.2018.01.023
Scopus EID2-s2.0-85042135530
Page range594 - 609
Research GroupMary MacKillop Institute for Health Research
Publisher's version
File Access Level
Controlled
Place of publicationUnited States of America
Permalink -

https://acuresearchbank.acu.edu.au/item/889w8/mitochondrial-mdm2-regulates-respiratory-complex-i-activity-independently-of-p53

Restricted files

Publisher's version

  • 62
    total views
  • 0
    total downloads
  • 1
    views this month
  • 0
    downloads this month
These values are for the period from 19th October 2020, when this repository was created.

Export as

Related outputs

SGC-CAMKK2-1 : A chemical probe for CAMKK2
Wells, Carrow, Liang, Yi, Pulliam, Thomas L., Lin, Chenchu, Awad, Dominik, Eduful, Benjamin, O’Byrne, Sean, Hossain, Mohammad Anwar, Catta-Preta, Carolina Moura Costa, Ramos, Priscila Zonzini, Gileadi, Opher, Gileadi, Carina, Couñago, Rafael M., Stork, Brittany, Langendorf, Christopher G., Nay, Kevin, Oakhill, Jonathan S., Mukherjee, Debarati, Racioppi, Luigi, ... Drewry, David H.. (2023). SGC-CAMKK2-1 : A chemical probe for CAMKK2. Cells. 12(2), p. Article 287. https://doi.org/10.3390/cells12020287
Oxidative and glycolytic skeletal muscles deploy protective mechanisms to avoid atrophy under pathophysiological iron overload
Martin, David, Nay, Kévin, Robin, François, Rebillard, Amélie, Orfila, Luz, Martin, Brice, Leroyer, Patricia, Guggenbuhl, Pascal, Dufresne, Suzanne, Noirez, Philippe, Ropert, Martine, Loréal, Olivier and Derbré, Frédéric. (2022). Oxidative and glycolytic skeletal muscles deploy protective mechanisms to avoid atrophy under pathophysiological iron overload. Journal of Cachexia, Sarcopenia and Muscle. 13(2), pp. 1250-1261. https://doi.org/10.1002/jcsm.12897
Molecular mechanisms underlying the beneficial effects of exercise on brain function and neurological disorders
Nay, Kévin, Smiles, William J., Kaiser, Jacqueline, McAloon, Luke M., Loh, Kim, Galic, Sandra, Oakhill, Jonathan S., Gundlach, Andrew L. and Scott, John W.. (2021). Molecular mechanisms underlying the beneficial effects of exercise on brain function and neurological disorders. International Journal of Molecular Sciences. 22, p. Article 4052. https://doi.org/10.3390/ijms22084052
Does physical inactivity induce significant changes in human gut microbiota? New answers using the dry immersion hypoactivity model
Jollet, Maxence, Nay, Kevin, Chopard, Angele, Bareille, Marie-Pierre, Beck, Arnaud, Ollendorff, Vincent, Vernus, Barbara, Bonnieu, Anne, Mariadassou, Mahendra, Rué, Olivier, Derbré, Frédéric, Goustard, Bénédicte and Koechlin-Ramonatxo, Christelle. (2021). Does physical inactivity induce significant changes in human gut microbiota? New answers using the dry immersion hypoactivity model. Nutrients. 13(11), p. Article 3865. https://doi.org/10.3390/nu13113865
Hinge binder scaffold hopping identifies potent calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitor chemotypes
Eduful, Benjamin J., O'Byrne, Sean N., Temme, Louisa, Asquith, Christopher R. M., Liang, Yi, Picado, Alfredo, Pilotte, Joseph R., Hossain, Mohammad Anwar, Wells, Carrow I., Zuercher, William J., Catta-Preta, Carolina M.C, Ramos, Priscila, de S. Santiago, André, Counago, Rafael M., Langendorf, Christopher G., Nay, Kevin, Oakhill, Jonathan S., Pulliam, Thomas L., Lin, Chenchu, ... Drewry, David H.. (2021). Hinge binder scaffold hopping identifies potent calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitor chemotypes. Journal of Medicinal Chemistry. 64(15), pp. 10849-10877. https://doi.org/10.1021/acs.jmedchem.0c02274
Intermittent reloading does not prevent reduction in iron availability and hepcidin upregulation caused by hindlimb unloading
Nay, Kévin, Martin, David, Orfila, Luz, Saligaut, Dany, Martin, Brice, Horeau, Mathieu, Cavey, Thibaut, Kenawi, Moussa, Island, Marie-Laure, Ropert, Martine, Loréal, Olivier, Koechlin-Ramonatxo, Christelle and Derbré, Frédéric. (2021). Intermittent reloading does not prevent reduction in iron availability and hepcidin upregulation caused by hindlimb unloading. Experimental Physiology. 106(1), pp. 28-36. https://doi.org/10.1113/EP088339
Simulated microgravity disturbs iron metabolism and distribution in humans : Lessons from dry immersion, an innovative ground-based human model
Nay, Kévin, Koechlin-Ramonatxo, Christelle, Rochdi, Sarah, Island, Marie-Laure, Orfila, Luz, Treffel, Loïc, Bareille, Marie-Pierre, Beck, Arnaud, Gauquelin-Koch, Guillemette, Ropert, Martine, Loréal, Olivier and Derbré, Frédéric. (2020). Simulated microgravity disturbs iron metabolism and distribution in humans : Lessons from dry immersion, an innovative ground-based human model. The FASEB Journal. 34(11), pp. 14920-14929. https://doi.org/10.1096/fj.202001199RR
Gut bacteria are critical for optimal muscle function: A potential link with glucose homeostasis
Nay, Kevin, Jollet, Maxence, Goustard, Benedicte, Baati, Narjes, Vernus, Barbara, Pontones, Maria, Lefeuvre-Orfila, Luz, Bendavid, Claude, Rué, Olivier, Mariadassou, Mahendra, Bonnieu, Anne, Ollendorff, Vincent, Lepage, Patricia, Derbré, Frédéric and Koechlin-Ramonatxo, Christelle. (2019). Gut bacteria are critical for optimal muscle function: A potential link with glucose homeostasis. American Journal of Physiology - Endocrinology and Metabolism. 317(1), pp. 158 - 171. https://doi.org/10.1152/ajpendo.00521.2018
Skeletal muscle ceramides do not contribute to physical-inactivity-induced insulin resistance
Appriou, Zéphyra, Nay, Kevin, Pierre, Nicolas, Saligaut, Dany, Lefeuvre-Orfila, Luz, Martin, Brice, Cavey, Thibault, Ropert, Martine, Loréal, Olivier, Rannou-Bekono, Françoise and Derbré, Frédéric. (2019). Skeletal muscle ceramides do not contribute to physical-inactivity-induced insulin resistance. Applied Physiology, Nutrition and Metabolism. 44(11), pp. 1180 - 1188. https://doi.org/10.1139/apnm-2018-0850
Ceruloplasmin deficiency does not induce macrophagic iron overload: Lessons from a new rat model of hereditary aceruloplasminemia
Kenawi, Moussa, Rouger, Emmanuel, Island, Marie-Laure, Leroyer, Patricia, Robin, François, Rémy, Séverine, Tesson, Laurent, Anegon, Ignacio, Nay, Kevin, Derbré, Frédéric, Brissot, Pierre, Ropert, Martine, Cavey, Thibault and Loréal, Olivier. (2019). Ceruloplasmin deficiency does not induce macrophagic iron overload: Lessons from a new rat model of hereditary aceruloplasminemia. The FASEB Journal. 33(12), pp. 13492 - 13502. https://doi.org/10.1096/fj.201901106R