Griparic Lorena, van der Wel Nicole N, Orozco Ian J, Peters Peter J, van der Bliek Alexander M
Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA.
J Biol Chem. 2004 Apr 30;279(18):18792-8. doi: 10.1074/jbc.M400920200. Epub 2004 Feb 16.
Mgm1 is a member of the dynamin family of GTP-binding proteins. Mgm1 was first identified in yeast, where it affects mitochondrial morphology. The human homologue of Mgm1 is called OPA1. Mutations in the OPA1 gene are the prevailing cause of dominant optic atrophy, a hereditary disease in which progressive degeneration of the optic nerve can lead to blindness. Here we investigate the properties of the Mgm1/OPA1 protein in mammalian cells. We find that Mgm1/OPA1 is localized to the mitochondrial intermembrane space, where it is tightly bound to the outer surface of the inner membrane. Overexpression of wild type or mutant forms of the Mgm1/OPA1 protein cause mitochondria to fragment and, in some cases, cluster near the nucleus, whereas the loss of protein caused by small interfering RNA (siRNA) leads to dispersal of mitochondrial fragments throughout the cytosol. The cristae of these fragmented mitochondria are disorganized. At early time points after transfection with Mgm1/OPA1 siRNA, the mitochondria are not yet fragmented. Instead, the mitochondria swell and stretch, after which they form localized constrictions similar to the mitochondrial abnormalities observed during the early stages of apoptosis. These abnormalities might be the earliest effects of losing Mgm1/OPA1 protein.
Mgm1是GTP结合蛋白的发动蛋白家族成员。Mgm1最初在酵母中被鉴定出来，它在酵母中影响线粒体形态。Mgm1的人类同源物被称为OPA1。OPA1基因的突变是显性视神经萎缩的主要病因，显性视神经萎缩是一种遗传性疾病，其中视神经的进行性退化可导致失明。在这里，我们研究了Mgm1/OPA1蛋白在哺乳动物细胞中的特性。我们发现Mgm1/OPA1定位于线粒体内膜间隙，紧密结合在内膜的外表面。野生型或突变型Mgm1/OPA1蛋白的过表达会导致线粒体碎片化，在某些情况下，会聚集在细胞核附近，而小干扰RNA（siRNA）导致的蛋白缺失会导致线粒体碎片分散在整个细胞质中。这些碎片化线粒体的嵴是无序的。在用Mgm1/OPA1 siRNA转染后的早期时间点，线粒体尚未碎片化。相反，线粒体肿胀并伸展，之后形成局部收缩，类似于在细胞凋亡早期观察到的线粒体异常。这些异常可能是失去Mgm1/OPA1蛋白的最早影响。
