Mitochondrial fission proteins regulate programmed cell death in yeast
Mitochondrial fission proteins regulate programmed cell death in yeast
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DOI：
10.1101/gad.1247904
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发表时间：
2004-11-15
影响因子：
10.5
通讯作者：
Hardwick, JM
中科院分区：
文献类型：
--
作者：
Fannjiang, Y;Cheng, WC;Hardwick, JM
单细胞生物经历程序性细胞死亡的可能性一直受到质疑，部分原因是它们缺乏哺乳动物细胞死亡机制的几个关键组成部分。然而，酵母编码了人类Drp1的同源物，Drp1是一种线粒体裂变蛋白，先前被证明可以促进哺乳动物细胞死亡和哺乳动物细胞凋亡的线粒体过度断裂特征。为了支持涉及线粒体的程序性细胞死亡的原始起源，我们发现酿酒酵母与人类Drp1的同源物Dnm1在几种死亡刺激处理后促进线粒体断裂/降解和细胞死亡。两个dnm1相互作用的因子也调节酵母细胞死亡。WD40重复蛋白Mdv1/Net2促进细胞死亡，与其在线粒体裂变中的作用一致。与其在健康细胞中的裂变功能相反，Fis1在酵母中出人意料地抑制dnm1介导的线粒体裂变和半胱氨酸蛋白酶依赖的细胞死亡。此外，酵母Fis1抑制线粒体分裂和细胞死亡的能力在功能上可以被人Bcl-2和Bcl-x(L)取代。总之，这些发现表明酵母和哺乳动物细胞有一个保守的程序性死亡途径，该途径由一个共同的分子成分Drp1/Dnm1调节，该成分被bcl -2样功能抑制。
The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we found that the Saccharomyces cerevisiae homolog of human Drp1, Dnm1, promotes mitochondrial fragmentation/degradation and cell death following treatment with several death stimuli. Two Dnm1-interacting factors also regulate yeast cell death. The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission. In contrast to its fission function in healthy cells, Fis1 unexpectedly inhibits Dnm1-mediated mitochondrial fission and cysteine protease-dependent cell death in yeast. Furthermore, the ability of yeast Fis1 to inhibit mitochondrial fission and cell death can be functionally replaced by human Bcl-2 and Bcl-x(L). Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function.