Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility.
Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility.
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DOI：
10.1016/j.cub.2011.03.030
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发表时间：
2011-04-26
期刊：
影响因子：
9.2
通讯作者：
Pol, Albert
中科院分区：
文献类型：
--
作者：
Bosch, Marta;Mari, Montserrat;Herms, Albert;Fernandez, Ana;Fajardo, Alba;Kassan, Adam;Giralt, Albert;Colell, Anna;Balgoma, David;Barbero, Elisabet;Gonzalez-Moreno, Elena;Matias, Nuria;Tebar, Francesc;Balsinde, Jesus;Camps, Marta;Enrich, Carlos;Gross, Steven P.;Garcia-Ruiz, Carmen;Perez-Navarro, Esther;Fernandez-Checa, Jose C.;Pol, Albert
Caveolins（CAV）是Caveolae的重要组成部分;质膜内陷具有降低的流动性，反映胆固醇积聚。CAV蛋白结合胆固醇，CAV在细胞间移动的能力有助于控制细胞内胆固醇的流动。在人类中，CAV 1突变导致脂肪营养不良、细胞转化和癌症。CAV 1基因被破坏的小鼠表现出心血管疾病、糖尿病、癌症、动脉粥样硬化和肺纤维化。这些不同影响的机制尚不清楚，但我们过去的工作表明CAV 1缺乏可能会改变代谢：CAV 1 −/−小鼠表现出肝再生受损，除非补充葡萄糖，这表明系统性效率低下需要额外的代谢中间体。建立CAV 1和代谢之间的功能联系将提供一个统一的主题来解释这些无数的病理。在这里，我们证明了葡萄糖限制的增殖受损和低存活率是CAV 1缺陷细胞的一个缺点，由线粒体功能受损引起。如果没有CAV 1，游离胆固醇在线粒体膜中积累，增加膜浓缩并降低呼吸链和内在抗氧化防御的效率。在氧化磷酸化活化后，这促进活性氧物质的积累，导致细胞死亡。我们证实，这种线粒体功能障碍易使CAV 1缺陷动物发生线粒体相关疾病，如脂肪性肝炎和神经变性。
Caveolins (CAV) are essential components of caveolae; plasma membrane invaginations with reduced fluidity, reflecting cholesterol accumulation. CAV proteins bind cholesterol, and CAV’s ability to move between cellular compartments helps control intracellular cholesterol fluxes. In humans, CAV1 mutations result in lipodystrophy, cell transformation, and cancer. CAV1 gene-disrupted mice exhibit cardiovascular diseases, diabetes, cancer, atherosclerosis, and pulmonary fibrosis. The mechanism(s) underlying these disparate effects are unknown, but our past work suggested CAV1 deficiency might alter metabolism: CAV1−/− mice exhibit impaired liver regeneration unless supplemented with glucose, suggesting systemic inefficiencies requiring additional metabolic intermediates. Establishing a functional link between CAV1 and metabolism would provide a unifying theme to explain these myriad pathologies. Here, we demonstrate that impaired proliferation and low survival with glucose restriction is a shortcoming of CAV1 deficient cells, caused by impaired mitochondrial function. Without CAV1, free cholesterol accumulates in mitochondrial membranes, increasing membrane condensation and reducing efficiency of the respiratory chain and intrinsic anti-oxidant defence. Upon activation of oxidative phosphorylation, this promotes accumulation of reactive oxygen species resulting in cell death. We confirm that this mitochondrial dysfunction predisposes CAV1 deficient animals to mitochondrial related diseases such as steatohepatitis and neurodegeneration.
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DOI：
10.1038/labinvest.2009.23
发表时间：
2009-06
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
线粒体能量和治疗学。
DOI：
10.1146/annurev.pathol.4.110807.092314
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Wallace DC;Fan W;Procaccio V
通讯作者：
Procaccio V
影响因子：
15.9
作者：
Jefcoate, C
通讯作者：
Jefcoate, C
影响因子：
5.8
作者：
Kim, C. A.;Delepine, Marc;Magre, Jocelyne
通讯作者：
Magre, Jocelyne
影响因子：
4.8
作者：
Gonzalez-Munoz, Elena;Lopez-Iglesias, Carmen;Camps, Marta
通讯作者：
Camps, Marta