Bcl-2 prevents mitochondrial permeability transition and cytochrome c release via maintenance of reduced pyridine nucleotides
Bcl-2 prevents mitochondrial permeability transition and cytochrome c release via maintenance of reduced pyridine nucleotides
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DOI：
10.1038/sj.cdd.4400722
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发表时间：
2000-10-01
影响因子：
12.4
通讯作者：
Fiskum, G
中科院分区：
文献类型：
--
作者：
Kowaltowski, A;Vercesi, AE;Fiskum, G
在Ca2+和线粒体通透性转变（MPT）诱导剂t-丁基过氧化氢（t-bOOH）或氧化苯larsin （PhAsO）存在的情况下，黄地黄苷通透化的PC12和GT1-7神经细胞表现出环孢素a敏感的线粒体膜电位下降、体积增加和促凋亡因子细胞色素c的释放。虽然诱导MPT所需的PhAsO浓度在Bcl-2阴性和Bcl-2过表达转染细胞（Bcl-2(+)）中相似，但触发MPT所需的t-bOOH水平在Bcl-2（+）细胞中要高得多，更高浓度的t-bOOH也需要促进Bcl-2（+）细胞中线粒体吡呤核苷酸的氧化。Bcl-2（-）细胞线粒体对t-bOOH而不是PhAsO的敏感性可以通过使用保护吡啶核苷酸抗氧化的条件来克服。我们得出结论，Bcl-2（+）细胞在Ca2+ t-bOOH诱导的氧化应激条件下，Bcl-2（+）细胞维持线粒体吡啶核苷酸在还原氧化还原状态的能力增强，足以解释它们对MPT的抗性。
Digitonin-permeabilized PC12 and GT1-7 neural cells exhibited a cyclosporin A-sensitive decrease in mitochondrial membrane potential, increased volume, and release of the proapoptotic factor cytochrome c in the presence of Ca2+ and the mitochondrial permeability transition (MPT) inducers t-butyl hydroperoxide (t-bOOH) or phenylarsine oxide (PhAsO). Although the concentration of PhAsO required to induce the MPT was similar for Bcl-2 negative and Bcl-2 overexpressing transfected cells (Bcl-2(+)), the level of t-bOOH necessary for triggering the MPT was much hi gh er for Bcl-2(+) cells, A higher concentration of t-bOOH was also necessary for promoting the oxidation of mitochondrial pyridine nucleotides in Bcl-2(+) cells. The sensitivity of Bcl-2(-)cell mitochondria to t-bOOH but not PhAsO could be overcome by the use of conditions that protect the pyridine nucleotides against oxidation, We conclude that the increased ability of Bcl-2(+) cells to maintain mitochondrial pyridine nucleotides in a reduced redox state is sufficient explanation for their resistance to MPT under conditions of oxidative stress induced by Ca2+ plus t-bOOH.