The mitochondrial inner membrane protein mitofilin controls cristae morphology
The mitochondrial inner membrane protein mitofilin controls cristae morphology
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DOI：
10.1091/mbc.e04-08-0697
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发表时间：
2005-03-01
影响因子：
3.3
通讯作者：
Zha, JP
中科院分区：
文献类型：
--
作者：
John, GB;Shang, YL;Zha, JP
线粒体是具有高度动态分布和内部组织的复杂细胞器。在这里，我们证明有丝分裂蛋白，一种先前鉴定的功能未知的线粒体蛋白，控制线粒体嵴形态。有丝分裂蛋白在内边界和外膜之间的狭窄空间中富集，在那里它形成同型相互作用并组装成一个大的多聚体蛋白复合物。通过特异性小干扰RNA下调HeLa细胞的mitofilin，导致细胞增殖减少，凋亡增加，提示线粒体功能异常。虽然线粒体分裂和融合看起来正常，但超微结构研究显示线粒体内膜紊乱。内膜不能形成管状或泡状嵴，表现为紧密堆积的膜片，间歇性融合，形成复杂的迷宫状膜网。电镜断层扫描估计内外膜比例大幅增加，而没有检测到嵴连接。此外，线粒体随后表现出活性氧的产生和膜电位的增加。虽然代谢通量因有丝分裂蛋白缺乏而增加，但线粒体氧化磷酸化并未相应增加。我们认为有丝分裂蛋白是线粒体嵴形态的关键组织者，因此对正常的线粒体功能是不可或缺的。
Mitochondria are complex organelles with a highly dynamic distribution and internal organization. Here, we demonstrate that mitofilin, a previously identified mitochondrial protein of unknown function, controls mitochondrial cristae morphology. Mitofilin is enriched in the narrow space between the inner boundary and the outer membranes, where it forms a homotypic interaction and assembles into a large multimeric protein complex. Down-regulation of mitofilin in HeLa cells by using specific small interfering RNA lead to decreased cellular proliferation and increased apoptosis, suggesting abnormal mitochondrial function. Although gross mitochondrial fission and fusion seemed normal, ultrastructural studies revealed disorganized mitochondrial inner membrane. Inner membranes failed to form tubular or vesicular cristae and showed as closely packed stacks of membrane sheets that fused intermittently, resulting in a complex maze of membranous network. Electron microscopic tomography estimated a substantial increase in innevouter membrane ratio, whereas no cristae junctions were detected. In addition, mitochondria subsequently exhibited increased reactive oxygen species production and membrane potential. Although metabolic flux increased due to mitofilin deficiency, mitochondrial oxidative phosphorylation was not increased accordingly. We propose that mitofilin is a critical organizer of the mitochondrial cristae morphology and thus indispensable for normal mitochondrial function.