Inverse correlation between expression of the Wolfs Hirschhorn candidate gene Letm1 and mitochondrial volume in C-elegans and in mammalian cells
Inverse correlation between expression of the Wolfs Hirschhorn candidate gene Letm1 and mitochondrial volume in C-elegans and in mammalian cells
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DOI：
10.1093/hmg/ddm154
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发表时间：
2007-09-01
影响因子：
3.5
通讯作者：
van der Bliek, Alexander M.
中科院分区：
文献类型：
--
作者：
Hasegawa, Ayako;van der Bliek, Alexander M.
Letm1 基因的缺失与 Wolf-Hirschhorn 综合征患者癫痫的发生相关。 Letm1 基因编码与酵母 Mdm38 同源的线粒体蛋白。酵母 Mdm38 定位于线粒体内膜，在那里它被提议充当 K+/H+ 反向转运蛋白或作为选定线粒体内膜蛋白的伴侣。在这里，我们展示了哺乳动物细胞中 Letm1 的细胞和生化分析，以及对可作为 Wolf-Hirschhorn 综合征模型的秀丽隐杆线虫突变体的分析。我们将 Letm1 蛋白定位于哺乳动物细胞的线粒体内膜，它以 550 kDa 的复合物形式存在。我们证明 Letm1 可以在体外与其自身结合，这提高了它在体内形成更高阶多聚体的可能性。人类细胞和线虫中 Letm1 水平降低会导致线粒体长度肿胀，这与在酵母中观察到的表型一致。电子显微照片显示线粒体具有肿胀的基质，其电子密度低于正常线粒体中的基质。 Letm1 的过度表达可达到相反的效果。过度表达会增加线粒体基质的电子密度和嵴肿胀。因此，我们的结果与调节线粒体基质体积的蛋白质一致。
Deletion of the Letm1 gene correlates with the occurrence of epilepsy in patients with Wolf-Hirschhorn syndrome. The Letm1 gene encodes a mitochondrial protein that is homologous to yeast Mdm38. Yeast Mdm38 is localized to the mitochondrial inner membrane where it was proposed to act as a K+/H+ antiporter or alternatively as a chaperone for selected mitochondrial inner membrane proteins. Here, we present cellular and biochemical analysis of Letm1 in mammalian cells and an analysis of a C. elegans mutant that could serve as a model for Wolf-Hirschhorn syndrome. We localized the Letm1 protein to the mitochondrial inner membrane of mammalian cells, where it exists in a 550-kDa complex. We show that Letm1 can bind to itself in vitro, raising the possibility that it can form higher order multimers in vivo. Reduced levels of Letm1 in human cells and in, C. elegans lead to swellings along the lengths of mitochondria, consistent with the phenotype observed in yeast. Electron micrographs show mitochondria with swollen matrices that are less electron-dense than matrices in normal mitochondria. The opposite effect is achieved by overexpression of Letm1. Overexpression increases the electron density of the mitochondrial matrix and swelling of cristae. Our results are therefore consistent with a protein that regulates the volume of the mitochondrial matrix.