Cholesterol, Cardiolipin, and Mitochondria Permeabilisation
Cholesterol, Cardiolipin, and Mitochondria Permeabilisation
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DOI：
10.2174/187152012800228724
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发表时间：
2012-05-01
影响因子：
2.8
通讯作者：
Haesler, Safa Lucken-Ardjomande
中科院分区：
文献类型：
--
作者：
Haesler, Safa Lucken-Ardjomande
细胞凋亡是一种程序性细胞死亡的形式，是多细胞生物发育和正常功能所必需的。它是由一种叫做半胱天半酶的蛋白酶家族的激活引起的形态和生化修饰的结合来定义的。有几种途径可导致caspase激活，它们通常涉及通常隔离在线粒体膜间隙的凋亡因子的释放。线粒体促凋亡因子的完全释放最终导致细胞死亡，无论是以caspase依赖还是独立的方式。因此，严格控制线粒体的通透性是必要的。这一过程的调节因子的突变，如Bcl-2家族的蛋白质，确实在许多癌症中都有报道。此外，脂质作为蛋白质活动的调节器和作为毛孔本身的组成部分，其作用也开始被揭示出来。早期，线粒体特异性磷脂cardiolipin作为Bcl-2家族促凋亡蛋白的靶向信号的作用被发现。随着研究表明心磷脂也支持Bcl-2家族蛋白的构象变化，作为额外的促凋亡因子的对接站，并且对于激活Bax和Bak的合成脂质体的渗透性至关重要，因此心磷脂的作用得到了扩展。最近，胆固醇水平在大多数癌细胞中升高，被证明有助于它们抵抗细胞毒性压力。因此，降低胆固醇水平可能是使癌细胞对化疗药物敏感的一个有趣的新靶点。
Apoptosis is a form of programmed cell death required for the development and for the proper functioning of multicellular organisms. It is defined by a combination of morphological and biochemical modifications that result from the activation of a family of proteases called caspases. Several pathways can lead to caspase activation and they often involve the release of apoptogenic factors normally sequestered in the mitochondrial intermembrane space. Complete release of mitochondrial pro-apoptotic factors ultimately results in cell death, whether in a caspase-dependent or independent manner. A tight control of mitochondrial permeability is therefore essential. Mutations of regulators of the process, such as proteins of the Bcl-2 family, have indeed been reported in many cancers. In addition, the contributions of lipids, both as regulators of protein activities and as components of the pore itself, are starting to be unravelled. Early on, the role of the mitochondria-specific phospholipid cardiolipin as a targeting signal for pro-apoptotic proteins of the Bcl-2 family was discovered. This role was then expanded since it was shown that cardiolipin also supports conformational changes undergone by proteins of the Bcl-2 family, serves as a docking station for additional pro-apoptotic factors, and is essential for the permeabilisation of synthetic liposomes by activated Bax and Bak. More recently, cholesterol, whose level is increased in most cancer cells, was shown to contribute to their resistance to cytotoxic stresses. Reducing cholesterol levels might therefore represent an interesting novel target to sensitize cancer cells to chemotherapeutic agents.