Abstract
Optic atrophy 1 (OPA1) is a dynamin-like GTPase located in the inner mitochondrial membrane and mutations in OPA1 are associated with autosomal dominant optic atrophy (DOA). OPA1 plays important roles in mitochondrial fusion, cristae remodeling and apoptosis. Our previous study showed that dOpa1 mutation caused elevated reactive oxygen species (ROS) production and resulted in damage and death of the cone and pigment cells in Drosophila eyes. Since ROS-induced oxidative damage to the cells is one of the primary causes of aging, in this study, we examined the effects of heterozygous dOpa1 mutation on the lifespan. We found that heterozygous dOpa1 mutation caused shortened lifespan, increased susceptibility to oxidative stress and elevated production of ROS in the whole Drosophila. Antioxidant treatment partially restored lifespan in the male dOpa1 mutants, but had no effects in the females. Heterozygous dOpa1 mutation caused an impairment of respiratory chain complex activities, especially complexes II and III, and reversible decreased aconitase activity. Heterozygous dOpa1 mutation is also associated with irregular and dysmorphic mitochondria in the muscle. Our results, for the first time, demonstrate the important role of OPA1 in aging and lifespan, which is most likely mediated through augmented ROS production.
Highlights
Optic atrophy 1 (OPA1) is a ubiquitously expressed large dynamin-related GTPase, encoded by the nuclear genome and targeted to the inner mitochondrial membrane [1,2,3]
To test the hypothesis that heterozygous mutation of dOpa1 affects the lifespan in Drosophila, we performed a longevity assay on a large cohort (n = 300/genotype) of dOpa1+/2 and dOpa1+/+ control Drosophila
We previously showed that the P-element insertion in exon 2 and transposon insertion in intron 3 disrupted dOpa1 expression while insertion in non-coding exon 14 had no effect on the dOpa1 protein level, dOpa1+/ex14 served as a control
Summary
OPA1 is a ubiquitously expressed large dynamin-related GTPase, encoded by the nuclear genome and targeted to the inner mitochondrial membrane [1,2,3]. Mutations of OPA1 cause dominant optic atrophy (DOA), the most common form of autosomal inherited optic neuropathy. In the eye-specific somatic clones, the somatic homozygous mutation of dOpa in the eyes caused rough (mispatterning) and glossy (decreased lens and pigment deposition) eye phenotypes in adult Drosophila. In Drosophila eyes, dOpa mutation resulted in elevated ROS generation and mitochondrial fragmentation associated with damage and death of the cone and pigment cells. Treatment with antioxidants or superoxide dismutase (SOD1), as well as over-expression of human SOD1 did reverse the glossy phenotype, further indicating the important role of ROS in etiology of optic atrophy
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