MAC and Bcl-2 family proteins conspire in a deadly plot.
MAC and Bcl-2 family proteins conspire in a deadly plot.
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DOI：
10.1016/j.bbabio.2010.01.007
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发表时间：
2010-06
影响因子：
4.3
通讯作者：
Kinnally, Kathleen W.
中科院分区：
文献类型：
--
作者：
Dejean, Laurent M.;Ryu, Shin-Young;Martinez-Caballero, Sonia;Teijido, Oscar;Peixoto, Pablo M.;Kinnally, Kathleen W.
细胞凋亡是细胞程序性死亡的一种基本形式，是高等真核生物的基础，也是控制组织稳态的机制所必需的。细胞凋亡还涉及许多病理学，包括癌症、神经退行性疾病、衰老和梗塞。该细胞死亡程序由Bcl-2家族蛋白通过控制线粒体凋亡诱导通道（MAC）的形成来严格调节。MAC的组装对应于线粒体外膜的透化，这是所谓的凋亡的承诺步骤。MAC提供了通过线粒体外膜的途径，用于从膜间隙释放细胞色素c和其他促凋亡因子。虽然抗凋亡Bcl-2的过表达消除了MAC活性，但促凋亡成员Bax和/或巴克的寡聚体是MAC的基本结构组分。通过直接膜片钳线粒体，用含有前哨tBid（Bax和巴克的直接激活剂）的微量移液器真实的监测来自Bax或巴克的MAC的组装。在此，各种高亲和力的MAC抑制剂（iMAC），可能被证明是至关重要的工具，在机制的研究，最近已被确定。这篇评论的重点是MAC活性的表征，其调节Bcl-2家族蛋白，并讨论如何MAC可以被打开或关闭取决于待治疗的病理。
Apoptosis is an elemental form of programmed cell death; it is fundamental to higher eukaryotes and essential to mechanisms controlling tissue homeostasis. Apoptosis is also involved in many pathologies including cancer, neurodegenerative diseases, aging, and infarcts. This cell death program is tightly regulated by Bcl-2 family proteins by controlling the formation of the mitochondrial apoptosis-induced channel or MAC. Assembly of MAC corresponds to permeabilization of the mitochondrial outer membrane, which is the so called commitment step of apoptosis. MAC provides the pathway through the mitochondrial outer membrane for the release of cytochrome c and other pro-apoptotic factors from the intermembrane space. While overexpression of anti-apoptotic Bcl-2 eliminates MAC activity, oligomers of the pro-apoptotic members Bax and/or Bak are essential structural component(s) of MAC. Assembly of MAC from Bax or Bak was monitored in real time by directly patch-clamping mitochondria with micropipettes containing the sentinel tBid, a direct activator of Bax and Bak. Herein, a variety of high affinity inhibitors of MAC (iMAC) that may prove to be crucial tools in mechanistic studies have recently been identified. This review focuses on characterization of MAC activity, its regulation by Bcl-2 family proteins, and a discussion of how MAC can be pharmacologically turned on or off depending on the pathology to be treated.
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