Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
PLoS One. 2013;8(3):e59218. doi: 10.1371/journal.pone.0059218. Epub 2013 Mar 14.
Opa1 catalyzes fusion of inner mitochondrial membranes and formation of the cristae. OPA1 mutations in humans lead to autosomal dominant optic atrophy. OPA1 knockout mice lose viability around embryonic day 9 from unknown reasons, indicating that OPA1 is essential for embryonic development. Zebrafish are an attractive model for studying vertebrate development and have been used for many years to describe developmental events that are difficult or impractical to view in mammalian models. In this study, Opa1 was successfully depleted in zebrafish embryos using antisense morpholinos, which resulted in disrupted mitochondrial morphology. Phenotypically, these embryos exhibited abnormal blood circulation and heart defects, as well as small eyes and small pectoral fin buds. Additionally, startle response was reduced and locomotor activity was impaired. Furthermore, Opa1 depletion caused bioenergetic defects, without impairing mitochondrial efficiency. In response to mitochondrial dysfunction, a transient upregulation of the master regulator of mitochondrial biogenesis, pgc1a, was observed. These results not only reveal a new Opa1-associated phenotype in a vertebrate model system, but also further elucidates the absolute requirement of Opa1 for successful vertebrate development.
OPA1 催化线粒体内膜融合和嵴的形成。人类的 OPA1 突变导致常染色体显性视神经萎缩。由于未知原因，OPA1 敲除小鼠在胚胎第 9 天左右丧失活力，这表明 OPA1 对胚胎发育至关重要。斑马鱼是研究脊椎动物发育的理想模型，多年来一直被用于描述在哺乳动物模型中难以或不切实际观察到的发育事件。在这项研究中，使用反义 morpholino 成功地耗尽了斑马鱼胚胎中的 Opa1，导致线粒体形态异常。表型上，这些胚胎表现出异常的血液循环和心脏缺陷，以及小眼睛和小胸鳍芽。此外，惊跳反应减少，运动活性受损。此外，OPA1 的耗竭导致生物能量缺陷，而不损害线粒体效率。在对线粒体功能障碍的反应中，观察到线粒体生物发生的主调控因子 pgc1a 的短暂上调。这些结果不仅在脊椎动物模型系统中揭示了一种新的 Opa1 相关表型，还进一步阐明了 Opa1 对成功的脊椎动物发育的绝对要求。
