Limits...
Heterozygous mutation of Opa1 in Drosophila shortens lifespan mediated through increased reactive oxygen species production.

Tang S, Le PK, Tse S, Wallace DC, Huang T - PLoS ONE (2009)

Bottom Line: 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 is also associated with irregular and dysmorphic mitochondria in the muscle.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Genetics, Department of Pediatrics, University of California Irvine, Irvine, California, United States of America.

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.

Show MeSH

Related in: MedlinePlus

Heterozygous dOpa1 mutations shorten lifespan in Drosophila.The survival curves for Drosophila with P Element insertions in exon2 (dOpa1+/ex2), intron 3 (dOpa1+/in3), and exon 14 (dOpa1+/ex14) of dOpa1, as well as wild-type (dOpa1+/+) show that heterozygous mutations in exon 2 and intron 3 of dOpa1 significantly reduced both median and maximum lifespan. All dOpa1+/ex2 and dOpa1+/in3 Drosophila had died by Day 61.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2637430&req=5

pone-0004492-g001: Heterozygous dOpa1 mutations shorten lifespan in Drosophila.The survival curves for Drosophila with P Element insertions in exon2 (dOpa1+/ex2), intron 3 (dOpa1+/in3), and exon 14 (dOpa1+/ex14) of dOpa1, as well as wild-type (dOpa1+/+) show that heterozygous mutations in exon 2 and intron 3 of dOpa1 significantly reduced both median and maximum lifespan. All dOpa1+/ex2 and dOpa1+/in3 Drosophila had died by Day 61.

Mentions: 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+/− (dOpa1+/in3, dOpa1+/ex2) and dOpa1+/+ (dOpa1+/+ and dOpa1+/ex14) control Drosophila. We previously showed that the P-element insertion in exon 2 (dOpa1+/ex2) and transposon insertion in intron 3 (dOpa1+/in3) disrupted dOpa1 expression while insertion in non-coding exon 14 had no effect on the dOpa1 protein level, therefore, dOpa1+/ex14 also served as a control. Drosophila were maintained at 40–50 Drosophila/vial, transferred to fresh food and counted every 3 days. As shown in Figure 1, the dOpa1+/− mutant strain had a significant reduction in both average and maximum lifespan. Since there is no phenotypical difference between dOpa1+/in3 and dOpa1+/ex2, dOpa1+/in3 is referred as dOpa1+/− in all subsequent experiments. Wild-type Drosophila with the same background are used as the control and referred as dOpa1+/+.


Heterozygous mutation of Opa1 in Drosophila shortens lifespan mediated through increased reactive oxygen species production.

Tang S, Le PK, Tse S, Wallace DC, Huang T - PLoS ONE (2009)

Heterozygous dOpa1 mutations shorten lifespan in Drosophila.The survival curves for Drosophila with P Element insertions in exon2 (dOpa1+/ex2), intron 3 (dOpa1+/in3), and exon 14 (dOpa1+/ex14) of dOpa1, as well as wild-type (dOpa1+/+) show that heterozygous mutations in exon 2 and intron 3 of dOpa1 significantly reduced both median and maximum lifespan. All dOpa1+/ex2 and dOpa1+/in3 Drosophila had died by Day 61.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2637430&req=5

pone-0004492-g001: Heterozygous dOpa1 mutations shorten lifespan in Drosophila.The survival curves for Drosophila with P Element insertions in exon2 (dOpa1+/ex2), intron 3 (dOpa1+/in3), and exon 14 (dOpa1+/ex14) of dOpa1, as well as wild-type (dOpa1+/+) show that heterozygous mutations in exon 2 and intron 3 of dOpa1 significantly reduced both median and maximum lifespan. All dOpa1+/ex2 and dOpa1+/in3 Drosophila had died by Day 61.
Mentions: 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+/− (dOpa1+/in3, dOpa1+/ex2) and dOpa1+/+ (dOpa1+/+ and dOpa1+/ex14) control Drosophila. We previously showed that the P-element insertion in exon 2 (dOpa1+/ex2) and transposon insertion in intron 3 (dOpa1+/in3) disrupted dOpa1 expression while insertion in non-coding exon 14 had no effect on the dOpa1 protein level, therefore, dOpa1+/ex14 also served as a control. Drosophila were maintained at 40–50 Drosophila/vial, transferred to fresh food and counted every 3 days. As shown in Figure 1, the dOpa1+/− mutant strain had a significant reduction in both average and maximum lifespan. Since there is no phenotypical difference between dOpa1+/in3 and dOpa1+/ex2, dOpa1+/in3 is referred as dOpa1+/− in all subsequent experiments. Wild-type Drosophila with the same background are used as the control and referred as dOpa1+/+.

Bottom Line: 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 is also associated with irregular and dysmorphic mitochondria in the muscle.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Genetics, Department of Pediatrics, University of California Irvine, Irvine, California, United States of America.

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.

Show MeSH
Related in: MedlinePlus