Abstract
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.
Highlights
Optic Atrophy 1 (OPA1) is encoded by a ubiquitously expressed nuclear gene and localized in the inner mitochondrial membrane [1,2,3]
Our results suggest that heterozygous mutation of Drosophila OPA1 (dOpa1) could cause multiple organ abnormalities and that reactive oxygen species (ROS) may play a role in the development of some organs, but not others, suggesting that the pathogenesis could be organ specific
Loss of a single copy of dOpa1 did not elicit a gross eye phenotype other than morphologically perturbed mitochondria in transmission electron microscopy (TEM) [18]
Summary
OPA1 is encoded by a ubiquitously expressed nuclear gene and localized in the inner mitochondrial membrane [1,2,3]. OPA1 consists of a mitochondrial targeting signal (MTS), a transmembrane domain (TMD), a presenilin-associated rhomboid-like protease (PARL) site, and a dynamin/GTPase domain. The PARL can process OPA1, converting the insoluble inner mitochondrial membrane protein to a soluble protein [1,3]. Mutation of OPA1 causes retinal ganglion cell death and optic atrophy [4]. In a study of the sexinfluenced phenotype, we found that vision loss was more severe among affected males than females, and caused by the mutation IVS9 +2A.G in the OPA1 gene [16,17]
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