Mitochondrial MDM2 Regulates Respiratory Complex I Activity Independently of p53

被引：86

作者：

Arena, Giuseppe ^{[1
,2
,3
]}

Cisse, Madi Yann ^{[1
,2
]}

Pyrdziak, Samuel ^{[1
,2
]}

Chatre, Laurent ^{[3
]}

Riscal, Romain ^{[1
,2
]}

Fuentes, Maryse ^{[1
,2
]}

Arnold, Jamie Jon ^{[4
]}

Kastner, Markus ^{[4
]}

Gayte, Laurie ^{[1
,2
]}

Bertrand-Gaday, Christelle ^{[5
]}

Nay, Kevin ^{[5
]}

Angebault-Prouteau, Claire ^{[6
]}

Murray, Kerren ^{[7
]}

Chabi, Beatrice ^{[1
,5
]}

Koechlin-Ramonatxo, Christelle ^{[1
,5
]}

Orsetti, Beatrice ^{[2
]}

Vincent, Charles ^{[1
,2
]}

Casas, Francois ^{[5
]}

Marine, Jean-Christophe ^{[8
,9
]}

Etienne-Manneville, Sandrine ^{[7
]}

Bernex, Florence ^{[1
,10
]}

Lombes, Anne ^{[11
]}

Cameron, Craig Eugene ^{[4
]}

Dubouchaud, Herve ^{[12
]}

Ricchetti, Miria ^{[3
]}

Linares, Laetitia Karine ^{[1
,2
]}

Le Cam, Laurent ^{[1
,2
]}

机构：

[1] Univ Montpellier, Inst Reg Canc Montpellier, INSERM, Inst Rech Cancerol Montpellier, Montpellier, France

[2] Equipe Labelise Ligue Canc, Paris, France

[3] CNRS, Inst Pasteur, Team Stabil Nucl & Mitochondrial DNA, Dept Dev & Stem Cell Biol,Unit Stem Cells & Dev, Paris, France

[4] Penn State Univ, Dept Biochem & Mol Biol, State Coll, PA USA

[5] Univ Montpellier, INRA, Dynam Musculaire & Metab Lab, Montpellier, France

[6] Univ Montpellier, CHR, CNRS, INSERM, Montpellier, France

[7] INSERM, CNRS, Cell Polar Migrat & Canc Unit, Inst Pasteur Paris, Paris, France

[8] VIB, Ctr Biol Dis, Lab Mol Canc Biol, Leuven, Belgium

[9] Katholieke Univ Leuven, Dept Oncol, Lab Mol Canc Biol, Leuven, Belgium

[10] Univ Montpellier, INSERM, CNRS, Reseau Histol Expt Montpellier, BioCampus, Montpellier, France

[11] Univ Paris 05, CNRS, INSERM, Inst Cochin, Paris, France

[12] Univ Grenoble Alpes, INSERM, LBFA, Grenoble, France

来源：

MOLECULAR CELL | 2018年 / 69卷 / 04期

关键词：

SKELETAL-MUSCLE; PROTEIN IMPORT; APOPTOSIS; DNA; TRANSLOCATION; TRANSCRIPTION; METASTASIS; ACTIVATION; INITIATION; PROMOTES;

D O I：

10.1016/j.molcel.2018.01.023

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：594 / +

页数：24

共 40 条

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