Mitochondrial clustering induced by overexpression of fusion protein Mfn2 causes mitochondrial dysfunction the mitochondrial and cell death
Mitochondrial clustering induced by overexpression of fusion protein Mfn2 causes mitochondrial dysfunction the mitochondrial and cell death
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DOI：
10.1016/j.ejcb.2007.04.002
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发表时间：
2007-06-01
影响因子：
6.6
通讯作者：
Yoon, Yisang
中科院分区：
文献类型：
--
作者：
Huang, Pinwei;Yu, Tianzheng;Yoon, Yisang
线粒体主要通过分裂和融合动态地改变其形状。动力蛋白相关的GTP酶已被证明在这些过程中介导线粒体膜的重塑。这些GTP酶之一，线粒体融合蛋白，锚定在线粒体外膜上并介导外膜的融合。我们发现，过度表达的一个mitofusin isciform，Mfn 2，大大改变线粒体形态，形成线粒体簇。高分辨率显微镜检查表明，线粒体簇由小片段线粒体组成。抑制线粒体分裂阻止了簇的形成，支持线粒体簇是由分裂介导的线粒体碎裂和聚集形成的观点。线粒体簇显示内膜电位和线粒体功能降低，表明由Mfn 2过表达产生的小片段线粒体的功能妥协;然而，线粒体簇仍然保留线粒体DNA。我们发现，细胞含有群集线粒体失去细胞色素c从线粒体和半胱天冬酶介导的凋亡。这些结果表明，线粒体变形损害线粒体功能，导致凋亡性细胞死亡，并表明线粒体中存在复杂的形式-功能关系。(c)2007年，Elsevier GmbH。All rights reserved.
Mitochondria change their shapes dynamically mainly through fission and fusion. Dynamin-related GTPases have been shown to mediate remodeling of mitochondrial membranes during these processes. One of these GTPases, mitofusin, is anchored at the outer mitochondrial membrane and mediates fusion of the outer membrane. We found that overexpression of a mitofusin isciform, Mfn2, drastically changes mitochondrial morphology, forming mitochondrial clusters. High-resolution microscopic examination indicated that the mitochondrial clusters consisted of small fragmented mitochondria. Inhibiting mitochondrial fission prevented the cluster formation, Supporting the notion that mitochondrial clusters are formed by fission-mediated mitochondrial fragmentation and aggregation. Mitochondrial clusters displayed a decreased inner membrane potential and mitochondrial function, suggesting a functional compromise of small fragmented rnitochondria produced by Mfn2 overexpression; however, mitochondrial clusters still retained mitochondrial DNA. We found that cells containing clustered mitochondria lost cytochrome c from mitochondria and underwent caspase-mediated apoptosis. These results demonstrate that mitochondrial deformation impairs mitochondrial function, leading to apoptotic cell death and suggest the presence of an intricate form-function relationship in mitochondria. (c) 2007 Elsevier GmbH. All rights reserved.