A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics
A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics
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DOI：
10.1038/sj.emboj.7601249
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发表时间：
2006-08-09
期刊：
影响因子：
11.4
通讯作者：
Yanagi, Shigeru
中科院分区：
文献类型：
--
作者：
Yonashiro, Ryo;Ishido, Satoshi;Yanagi, Shigeru
在这项研究中，我们已经确定了一种新的线粒体泛素连接酶，指定MITOL，这是本地化的线粒体外膜。MITOL具有植物同源结构域（PHD）基序，负责E3泛素连接酶活性和预测的四个跨膜结构域。MITOL通过自身泛素化活性以PHD依赖的方式显示快速降解。稳定表达缺少泛素连接酶活性的MITOL突变体的HeLa细胞或通过小干扰RNA的MITOL缺陷细胞显示异常的线粒体形态，例如片段化，这表明MITOL功能障碍增强了线粒体分裂。事实上，显性负性表达的Drp1突变体阻断线粒体碎片诱导的MITOL耗竭。我们发现MITOL与线粒体分裂蛋白hFis1和Drp1相关并泛素化。脉冲追踪实验表明，MITOL过表达增加这些裂变蛋白的周转。此外，MITOL共过表达可逆转hFis1的过表达表型。我们的发现表明，MITOL通过控制线粒体裂变蛋白在线粒体动力学中起着关键作用。
In this study, we have identified a novel mitochondrial ubiquitin ligase, designated MITOL, which is localized in the mitochondrial outer membrane. MITOL possesses a Plant Homeo-Domain (PHD) motif responsible for E3 ubiquitin ligase activity and predicted four-transmembrane domains. MITOL displayed a rapid degradation by auto-ubiquitination activity in a PHD-dependent manner. HeLa cells stably expressing a MITOL mutant lacking ubiquitin ligase activity or MITOL-deficient cells by small interfering RNA showed an aberrant mitochondrial morphology such as fragmentation, suggesting the enhancement of mitochondrial fission by MITOL dysfunction. Indeed, a dominant-negative expression of Drp1 mutant blocked mitochondrial fragmentation induced by MITOL depletion. We found that MITOL associated with and ubiquitinated mitochondrial fission protein hFis1 and Drp1. Pulse-chase experiment showed that MITOL overexpression increased turnover of these fission proteins. In addition, overexpression phenotype of hFis1 could be reverted by MITOL co-overexpression. Our finding indicates that MITOL plays a critical role in mitochondrial dynamics through the control of mitochondrial fission proteins.