Mitochondrial release of the NADH dehydrogenase Ndi1 induces apoptosis in yeast.
Mitochondrial release of the NADH dehydrogenase Ndi1 induces apoptosis in yeast.
复制标题
DOI：
10.1091/mbc.e12-04-0281
复制
发表时间：
2012-11
影响因子：
3.3
通讯作者：
Zhou B
中科院分区：
文献类型：
--
作者：
Cui Y;Zhao S;Wu Z;Dai P;Zhou B
Ndi1是与胱天蛋白酶（caspase）非依赖性细胞凋亡诱导因子AMID同源的酵母蛋白，结果表明它是一种普遍且强效的酵母细胞凋亡因子。这种蛋白通常在呼吸作用的第一步发挥作用，但在受到胁迫时，其保护性的N端会被切割，随后从线粒体中逸出并转变为促凋亡蛋白。
酿酒酵母的NDI1基因编码线粒体内膜泛醌氧化还原酶，该酶在呼吸链中将电子从NADH转移至泛醌。此前我们发现，Ndi1是凋亡诱导因子（AIF）的酵母同源蛋白——线粒体相关死亡诱导因子（AMID），并表现出强大的促凋亡活性。在此我们证明，酿酒酵母的NDI1参与了多种测试刺激（包括过氧化氢、锰和乙酸）诱导的细胞凋亡，且不受Z - VAD - fmk（一种胱天蛋白酶抑制剂）的抑制。尽管Ndi1也参与呼吸作用，但其促凋亡特性与泛醌氧化还原酶活性是可分离的。在细胞凋亡过程中，Ndi1的N端在线粒体内被切割，这种激活形式随后逸出以执行其凋亡功能。N端的切割似乎对于充分展现凋亡活性至关重要，因为未切割形式的Ndi1对生长的抑制活性要低得多。因此，我们的研究结果表明Ndi1在酵母生死命运的转换中发挥着重要作用：在正常生长过程中，Ndi1将电子整合到电子传递链中，启动呼吸过程以生成ATP；而在受到胁迫时，它会切割掉具有毒性隔离作用的N端帽结构，从线粒体中释放出来，进而成为细胞杀手。
Ndi1, the yeast homologue of caspase-independent apoptosis inducer AMID, turns out to be a general, as well as a potent, yeast apoptotic factor. This protein normally acts at the first step in respiration but, when stressed, cleaves its protective N-terminal, escapes from the mitochondria, and switches to become apoptotic. Saccharomyces cerevisiae NDI1 codes for the internal mitochondrial ubiquinone oxidoreductase, which transfers electrons from NADH to ubiquinone in the respiratory chain. Previously we found that Ndi1 is a yeast homologue of the protein apoptosis-inducing factor–homologous mitochondrion-associated inducer of death and displays potent proapoptotic activity. Here we show that S. cerevisiae NDI1 is involved in apoptosis induced by various stimuli tested, including H2O2, Mn, and acetate acid, independent of Z-VAD-fmk (a caspase inhibitor) inhibition. Although Ndi1 also participates in respiration, its proapoptotic property is separable from the ubiquinone oxidoreductase activity. During apoptosis, the N-terminal of Ndi1 is cleaved off in the mitochondria, and this activated form then escapes out to execute its apoptotic function. The N-terminal cleavage appears to be essential for the manifestation of the full apoptotic activity, as the uncleaved form of Ndi1 exhibits much less growth-inhibitory activity. Our results thus indicate an important role of Ndi1 in the switch of life and death fates in yeast: during normal growth, Ndi1 assimilates electrons to the electron transport chain and initiates the respiration process to make ATP, whereas under stresses, it cleaves the toxicity-sequestering N-terminal cap, is released from the mitochondria, and becomes a cell killer.