Effects of OPA1 mutations mitochondrial morphology and apoptosis:: Relevance to ADOA pathogenesis
Effects of OPA1 mutations mitochondrial morphology and apoptosis:: Relevance to ADOA pathogenesis
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DOI：
10.1002/jcp.20950
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发表时间：
2007-05-01
影响因子：
5.6
通讯作者：
Belenguer, Pascale
中科院分区：
文献类型：
--
作者：
Olichow, Aurelien;Landes, Thomas;Belenguer, Pascale
为了表征I型常染色体显性视神经萎缩（ADOA）和OPAI功能障碍之间的分子联系，分析了这种发动蛋白的致病等位基因对线粒体形态和细胞凋亡的影响，无论是在受影响的个体的成纤维细胞中，还是在用类似突变体转染的HeLa细胞中。这些等位基因是GT3结构域中的错义取代（OPAI（G300 E）和OPAI（R290 Q））或GT3效应结构域的缺失（OPAI（Delta 58））。OPAI（R290 Q）成纤维细胞和OPAI（G300 E）转染的HeLa细胞中线粒体碎片和凋亡增加。OPAI（Delta 58）对成纤维细胞线粒体形态无明显影响，但可增加成纤维细胞对星形孢菌素的敏感性。在这些细胞中，OPAI蛋白的量是对照成纤维细胞中的一半。我们的结论是，GTdR突变体通过与野生型等位基因竞争整合到融合能力复合物中来发挥显性负效应，而C-末端截短的等位基因则通过单倍不足发挥作用。我们提出了一个模型，其中拮抗融合和裂变的力量保持线粒体网络，在形态上的限制，是兼容的细胞功能。在患有I型ADOA的患者的视网膜神经节细胞（RGC）中，OPAI驱动的融合不能充分对抗分裂，从而使它们对凋亡刺激更敏感并最终导致视神经变性。
To characterize the molecular links between type-I autosomal dominant optic atrophy (ADOA) and OPAI dysfunctions, the effects of pathogenic alleles of this dynamin on mitochondrial morphology and apoptosis were analyzed, either in fibroblasts from affected individuals, or in HeLa cells transfected with similar mutants. The alleles were missense substitutions in the GTPase domain (OPAI(G300E) and OPAI(R290Q)) or deletion of the GTPase effector domain (OPAI(Delta 58)). Fragmentation of mitochondria and apoptosis increased in OPAI(R290Q) fibroblasts and in OPAI(G300E) transfected HeLa cells. OPAI(Delta 58) did not influence mitochondrial morphology, but increased the sensitivity to staurosporine of fibroblasts. In these cells, the amount of OPAI protein was half of that in control fibroblasts. We conclude that GTPase mutants exert a dominant negative effect by competing with wild-type alleles to integrate into fusion-competent complexes, whereas C-terminal truncated alleles act by haplo-insufficiency. We present a model where antagonistic fusion and fission forces maintain the mitochondrial network, within morphological limits that are compatible with cellular functions. In the retinal ganglion cells (RGCs) of patients suffering from type-I ADOA, OPAI-driven fusion cannot adequately oppose fission, thereby rendering them more sensitive to apoptotic stimuli and eventually leading to optic nerve degeneration.