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线粒体外膜孔道(电压依赖性阴离子通道)与腺嘌呤核苷酸转运体之间的复合物在能量代谢调控和细胞凋亡中的作用。

The function of complexes between the outer mitochondrial membrane pore (VDAC) and the adenine nucleotide translocase in regulation of energy metabolism and apoptosis.

作者信息

Vyssokikh Mikhail Y, Brdiczka Dieter

机构信息

A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia.

出版信息

Acta Biochim Pol. 2003;50(2):389-404.

Abstract

The outer mitochondrial membrane pore (VDAC) changes its structure either voltage-dependently in artificial membranes or physiologically by interaction with the adenine nucleotide translocase (ANT) in the c-conformation. This interaction creates contact sites and leads in addition to a specific organisation of cytochrome c in the VDAC-ANT complexes. The VDAC structure that is specific for contact sites generates a signal at the surface for several proteins in the cytosol to bind with high capacity, such as hexokinase, glycerol kinase and Bax. If the VDAC binding site is not occupied by hexokinase, the VDAC-ANT complex has two critical qualities: firstly, Bax gets access to cytochrome c and secondly the ANT is set in its c-conformation that easily changes conformation into an unspecific channel (uniporter) causing permeability transition. Activity of bound hexokinase protects against both, it hinders Bax binding and employs the ANT as anti-porter. The octamer of mitochondrial creatine kinase binds to VDAC from the inner surface of the outer membrane. This firstly restrains interaction between VDAC and ANT and secondly changes the VDAC structure into low affinity for hexokinase and Bax. Cytochrome c in the creatine kinase complex will be differently organised, not accessible to Bax and the ANT is run as anti-porter by the active creatine kinase octamer. However, when, for example, free radicals cause dissociation of the octamer, VDAC interacts with the ANT with the same results as described above: Bax-dependent cytochrome c release and risk of permeability transition pore opening.

摘要

线粒体外膜孔道(电压依赖性阴离子通道,VDAC)在人工膜中会随电压改变其结构,在生理状态下则通过与处于c构象的腺嘌呤核苷酸转运体(ANT)相互作用而改变结构。这种相互作用形成接触位点,此外还导致细胞色素c在VDAC-ANT复合物中形成特定的组织形式。对接触位点具有特异性的VDAC结构在表面产生一个信号,使几种胞质溶胶中的蛋白质能够高容量结合,如己糖激酶、甘油激酶和Bax。如果VDAC结合位点未被己糖激酶占据,VDAC-ANT复合物具有两个关键特性:首先,Bax能够接触到细胞色素c;其次,ANT处于其c构象,这种构象很容易转变为非特异性通道(单向转运体),从而导致通透性转换。结合的己糖激酶的活性可起到双重保护作用,它阻碍Bax结合,并使ANT作为反向转运体发挥作用。线粒体肌酸激酶八聚体从外膜内表面与VDAC结合。这首先抑制了VDAC与ANT之间的相互作用,其次将VDAC结构转变为对己糖激酶和Bax的低亲和力状态。肌酸激酶复合物中的细胞色素c会有不同的组织形式,Bax无法接触到它,并且活性肌酸激酶八聚体使ANT作为反向转运体发挥作用。然而,例如当自由基导致八聚体解离时,VDAC与ANT相互作用,结果与上述情况相同:Bax依赖的细胞色素c释放以及通透性转换孔开放的风险。

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