Phosphorylation of rat brain mitochondrial voltage-dependent anion as a potential tool to control leakage of cytochrome c
Phosphorylation of rat brain mitochondrial voltage-dependent anion as a potential tool to control leakage of cytochrome c
复制标题
DOI：
10.1111/j.1471-4159.2006.03853.x
复制
发表时间：
2006-08-01
影响因子：
4.7
通讯作者：
Ghosh, Subhendu
中科院分区：
文献类型：
--
作者：
Banerjee, Jyotirmoy;Ghosh, Subhendu
细胞凋亡是细胞死亡的受控形式，其参与发育、受损细胞的消除和细胞稳态的维持。此外，它在神经退行性疾病如阿尔茨海默病中起作用。最近，线粒体已成为控制细胞凋亡的关键。它们容纳许多致凋亡分子，如细胞色素c，在细胞凋亡开始时释放到细胞质中。当大鼠脑线粒体电压依赖性阴离子通道（VDAC），一种线粒体外膜蛋白，与Bcl-2家族蛋白Bax和tBid相互作用时，其孔径增加，导致细胞色素c和其他促凋亡分子释放到胞质溶胶中并引起细胞死亡。调节这种tBid-和tBid-诱导的VDAC孔径增加是控制细胞色素c诱导的细胞死亡的重要步骤。在这项工作中，我们已经表明，通过双层电生理学实验，VDAC电导的增加，由于其与Bax和tBid的相互作用是减少的，因为环AMP依赖性蛋白激酶A（PKA）在ATP的存在下的行动。这表明VDAC与Bax和tBid相互作用后的孔径增加是通过PKA对该通道的磷酸化控制的。我们相信，这可能是一种控制细胞色素c介导的活细胞死亡的机制。
Apoptosis is a controlled form of cell death that participates in development, elimination of damaged cells and maintenance of cell homeostasis. Also, it plays a role in neurodegenerative disorders like Alzheimer's disease. Recently, mitochondria have emerged as being pivotal in controlling apoptosis. They house a number of apoptogenic molecules, such as cytochrome c, which are released into the cytoplasm at the onset of apoptosis. When rat brain mitochondrial voltage-dependent anion channel (VDAC), an outer mitochondrial membrane protein, interacts with Bcl-2 family proteins Bax and tBid, its pore size increases, leading to the release of cytochrome c and other apoptogenic molecules into the cytosol and causing cell death. Regulation of this tBid- and Bax-induced increase in pore size of VDAC is a significant step to control cell death induced by cytochrome c. In this work, we have shown, through bilayer electrophysiological experiments, that the increase in VDAC conductance as a result of its interaction with Bax and tBid is reduced because of the action of cyclic AMP-dependent protein kinase A (PKA) in the presence of ATP. This indicates that the increase in the pore size of VDAC after its interaction with Bax and tBid is controlled via phosphorylation of this channel by PKA. This, we believe, could be a mechanism of controlling cytochrome c-mediated cell death in living cells.