| First Author | Arena G | Year | 2018 |
| Journal | Mol Cell | Volume | 69 |
| Issue | 4 | Pages | 594-609.e8 |
| PubMed ID | 29452639 | Mgi Jnum | J:260805 |
| Mgi Id | MGI:6150109 | Doi | 10.1016/j.molcel.2018.01.023 |
| Citation | Arena G, et al. (2018) Mitochondrial MDM2 Regulates Respiratory Complex I Activity Independently of p53. Mol Cell 69(4):594-609.e8 |
| abstractText | 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. |
