Heterozygous mutation of Drosophila Opa1 causes the development of multiple organ abnormalities in an age-dependent and organ-specific manner.
Heterozygous mutation of Drosophila Opa1 causes the development of multiple organ abnormalities in an age-dependent and organ-specific manner.
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DOI：
10.1371/journal.pone.0006867
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发表时间：
2009-08-31
期刊：
影响因子：
3.7
通讯作者：
Huang T
中科院分区：
文献类型：
--
作者：
Shahrestani P;Leung HT;Le PK;Pak WL;Tse S;Ocorr K;Huang T
视神经萎缩1 （Optic Atrophy 1, OPA1）是线粒体膜内普遍表达的动力蛋白样GTPase。它在线粒体融合、细胞凋亡、活性氧（ROS）和ATP产生中起重要作用。OPA1基因突变导致常染色体显性视神经萎缩（DOA）。连接OPA1突变和DOA的分子机制尚不完全清楚。最近，我们建立了一个果蝇模型来研究视神经萎缩的发病机制。通过p元素插入的杂合突变对果蝇OPA1 （dOpa1）没有明显的形态学异常，而纯合突变则具有胚胎致死性。在眼睛特异性体细胞克隆中，dOpa1的纯合突变导致成年果蝇眼睛表型粗糙（图案错误）和光滑（晶状体沉积减少）。在人类中，OPA1的杂合突变与线粒体功能障碍有关，预计会影响多个器官。在这项研究中，我们证明了杂合的dOpa1突变扰乱了果蝇复眼的视觉功能和ERG谱。我们独立地证明抗氧化剂延缓了ERG突变表型的发生，并在趋光实验中改善了幼虫的视觉功能。此外，杂合型dOpa1突变还会导致心率下降，心律失常增加，以及电起搏引起的应激耐受性差。然而，抗氧化剂对杂合子dOpa1突变体的功能失调心脏没有影响。在应激条件下，杂合子dOpa1突变导致逃避反应减少，提示骨骼肌功能异常。我们的研究结果表明，dOpa1的杂合突变具有器官特异性发病机制，并以年龄依赖性和器官特异性的方式与多器官异常相关。
Optic Atrophy 1 (OPA1) is a ubiquitously expressed dynamin-like GTPase in the inner mitochondrial membrane. It plays important roles in mitochondrial fusion, apoptosis, reactive oxygen species (ROS) and ATP production. Mutations of OPA1 result in autosomal dominant optic atrophy (DOA). The molecular mechanisms by which link OPA1 mutations and DOA are not fully understood. Recently, we created a Drosophila model to study the pathogenesis of optic atrophy. Heterozygous mutation of Drosophila OPA1 (dOpa1) by P-element insertion results in no obvious morphological abnormalities, whereas homozygous mutation is embryonic lethal. In eye-specific somatic clones, homozygous mutation of dOpa1 causes rough (mispatterning) and glossy (decreased lens deposition) eye phenotypes in adult Drosophila. In humans, heterozygous mutations in OPA1 have been associated with mitochondrial dysfunction, which is predicted to affect multiple organs. In this study, we demonstrated that heterozygous dOpa1 mutation perturbs the visual function and an ERG profile of the Drosophila compound eye. We independently showed that antioxidants delayed the onset of mutant phenotypes in ERG and improved larval vision function in phototaxis assay. Furthermore, heterozygous dOpa1 mutation also caused decreased heart rate, increased heart arrhythmia, and poor tolerance to stress induced by electrical pacing. However, antioxidants had no effects on the dysfunctional heart of heterozygous dOpa1 mutants. Under stress, heterozygous dOpa1 mutations caused reduced escape response, suggesting abnormal function of the skeletal muscles. Our results suggest that heterozygous mutation of dOpa1 shows organ-specific pathogenesis and is associated with multiple organ abnormalities in an age-dependent and organ-specific manner.
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影响因子：
11.2
作者：
Amati-Bonneau, P;Guichet, A;Reynier, P
通讯作者：
Reynier, P
DOI：
10.1073/pnas.0609278104
发表时间：
2007-03-06
影响因子：
11.1
作者：
Ocorr, Karen;Reeves, Nick L.;Bodmer, Rolf
通讯作者：
Bodmer, Rolf
影响因子：
2.6
作者：
GORGONE, G;LIVOLTI, S;MOLLICA, F
通讯作者：
MOLLICA, F
影响因子：
4.2
作者：
Amati-Bonneau, P;Odent, S;Bonneau, D
通讯作者：
Bonneau, D
影响因子：
14.5
作者：
Amati-Bonneau, Patrizia;Valentino, Maria Lucia;Carelli, Valerio
通讯作者：
Carelli, Valerio