Regulated necrotic cell death: the passive aggressive side of Bax and Bak.
Regulated necrotic cell death: the passive aggressive side of Bax and Bak.
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DOI：
10.1161/circresaha.116.305421
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发表时间：
2015-05-22
影响因子：
20.1
通讯作者：
Molkentin JD
中科院分区：
文献类型：
--
作者：
Karch J;Molkentin JD
在过去的30年里，细胞凋亡的分子效应分子在很大程度上被诠释，这使得人们对这一过程及其在细胞生物学中的重要性有了很强的生物学理解，但直到最近，细胞坏死死亡才被认为是一个类似的调控过程，具有可定义的分子效应。线粒体是细胞凋亡和调节性坏死的重要中枢介质。在细胞凋亡过程中，Bcl2家族成员Bax和Bak在线粒体膜外膜发生寡聚，导致诱导细胞凋亡的底物释放，半胱氨酸酶和核酸酶被激活。相反，在坏死期间，线粒体变得功能失调和适应不良，伴随着活性氧的产生和ATP的产生的丧失，部分原因是线粒体通透性转换孔的打开。虽然调节性坏死不依赖于caspase，但最近的证据表明，它仍然需要凋亡调节剂Bax和Bak，它们可以调节线粒体膜外非寡聚化状态的通透性。在这里，我们回顾了Bcl2家族的非凋亡面，特别是Bax和Bak在调节坏死性细胞死亡中的作用。我们还将讨论这些Bcl-2家族成员效应器如何成为一个更大的整合网络的一部分，该整合网络最终决定了特定细胞在凋亡和调节坏死之间的分子连续体中的某个位置的命运。
While the molecular effectors of apoptotic cell death have been largely annotated over the past 30 years, leading to a strong biologic understanding of this process and its importance in cell biology, cell death through necrosis has only recently been accepted as a similarly regulated process with definable molecular effectors. The mitochondria are important and central mediators of both apoptosis and regulated necrosis. In apoptosis the Bcl-2 family members Bax and Bak undergo oligomerization in the outer mitochondrial membrane resulting in the release of apoptosis inducing substrates and the activation of caspases and nucleases. In contrast, during necrosis the mitochondria become dysfunctional and maladaptive in conjunction with reactive oxygen species production and the loss of ATP production, in part through opening of the mitochondrial permeability transition pore. While regulated necrosis is caspase independent, recent evidence has shown that it still requires the apoptotic regulators Bax and Bak, which can regulate the permeability characteristics of the outer mitochondrial membrane in their non-oligomerized state. Here we review the non-apoptotic side of Bcl-2 family, specifically the role of Bax and Bak in regulated necrotic cell death. We will also discuss how these Bcl-2 family member effectors could be part of a larger integrated network that ultimately decides the fate of a given cell somewhere within a molecular continuum between apoptosis and regulated necrosis.