Insights into the mitochondrial signaling pathway: What lessons for chemotherapy?

被引:21
作者
Brenner, C
Le Bras, M
Kroemer, G
机构
[1] Univ Versailles St Quentin, CNRS, UPRESA 8087, LGBC Buffon, F-78035 Versailles, France
[2] Inst Gustave Roussy, CNRS, UMR 8125, F-94805 Villejuif, France
关键词
cell death; Bcl-2; mitochondria; permeability transition pore complex;
D O I
10.1023/A:1022541009662
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Mitochondria are potent integrators/coordinators of apoptosis signaling pathways. Indeed, under physiological conditions, the initiation of apoptosis leads to the accumulation of second messengers that converge on mitochondria. In response, these organelles undergo a membrane permeabilization, presumably due to the opening of protein channels, culminating in the release of proapoptotic proteins into the cytosol. Under pathological conditions, a failure of mitochondrial membrane permeabilization (MMP) can result in an inhibition of apoptosis and enhanced resistance to chemotherapy. Several non-mutually exclusive mechanisms may account for a defect in the execution or regulation of MMP. These include (i) alterations in gene transcription, (ii) gene mutations resulting in protein inactivation, and (iii) defects of intracellular localization. This may concern structural proteins of the permeability transition pore complex, as well as MMP regulatory proteins, such as Bax/Bcl-2 family members, p53, and cyclophilin D. Analysis of these mechanisms should improve our understanding of the basic function of mitochondria in apoptosis and help elaborate new strategies to correct MMP failure from a therapeutic perspective.
引用
收藏
页码:73 / 80
页数:8
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