Heterozygous mutation of Opa1 in Drosophila shortens lifespan mediated through increased reactive oxygen species production.
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.
Tang
Sha
S
Division of Human Genetics, Department of Pediatrics, University of California Irvine, Irvine, California, United States of America.
Le
Phung Khanh
PK
Tse
Stephanie
S
Wallace
Douglas C
DC
Huang
Taosheng
T
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D004579:Electron Transport / Q000235:genetics; D005260:Female; D006801:Humans; D008017:Life Expectancy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015996:Survival Rate
D000975:Antioxidants; D029721:Drosophila Proteins; D008565:Membrane Proteins; C527116:OPA1 protein, Drosophila; D017382:Reactive Oxygen Species