Unknown

Dataset Information

0

Mitochondrial MDM2 Regulates Respiratory Complex I Activity Independently of p53.


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.

SUBMITTER: Arena G 

PROVIDER: S-EPMC8215449 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC3694902 | biostudies-literature
| S-EPMC3958133 | biostudies-literature
| S-EPMC2842028 | biostudies-literature
| S-EPMC2528056 | biostudies-literature
| S-EPMC4772976 | biostudies-literature
| S-EPMC2928696 | biostudies-literature
| S-EPMC543405 | biostudies-other
| S-EPMC9817759 | biostudies-literature
| S-EPMC5499618 | biostudies-literature
| S-EPMC3141986 | biostudies-literature