Mitochondrial MDM2 Regulates Respiratory Complex I Activity Independently of p53.
Mol Cell
; 69(4): 594-609.e8, 2018 02 15.
Article
en En
| MEDLINE
| ID: mdl-29452639
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Regulación Neoplásica de la Expresión Génica
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Transformación Celular Neoplásica
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Proteína p53 Supresora de Tumor
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Carcinoma de Pulmón de Células no Pequeñas
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Complejo I de Transporte de Electrón
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Proteínas Proto-Oncogénicas c-mdm2
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Mitocondrias
Límite:
Animals
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Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article