RNA interference-mediated silencing of Sod2 in Drosophila leads to early adult-onset mortality and elevated endogenous oxidative stress.

Authors: Kirby K; Hu J; Hilliker AJ; Phillips JP

Abstract: Oxidative stress has been widely implicated as an important factor in the aging process. Because mitochondrial respiration is the principal source of reactive oxygen within cells, the mitochondrially localized superoxide dismutase (SOD) 2 is thought to play an important front-line defensive role against aging-related oxidative stress. Although genetic studies with mutants deficient in SOD1, the predominantly cytosolic isoform of SOD, have been instrumental in elucidating the role of reactive oxygen metabolism in aging in Drosophila, the lack of available mutations in the Sod2 gene has hampered an equivalent analysis of the participation of this important antioxidant enzyme in the Drosophila aging model. Here we report that ablation of mitochondrial SOD2 through expression of a GAL4-regulated, inverted-repeat Sod2 RNA-interference transgene in an otherwise normal animal causes increased endogenous oxidative stress, resulting in loss of essential enzymatic components of the mitochondrial respiratory chain and the tricarboxylic acid cycle, enhances sensitivity to applied oxidative stress, and causes early-onset mortality in young adults. In sharp contrast, ablation of SOD2 has no overt effect on the development of larvae and pupae, which may reflect a fundamental transition in oxygen utilization andor reactive oxygen metabolism that occurs during metamorphosis from larval to adult life.

Keywords: Animals; Citric Acid Cycle/genetics; DNA-Binding Proteins; Drosophila Proteins/*deficiency/genetics/physiology; Drosophila melanogaster/*enzymology/genetics/metabolism; Drug Resistance/genetics; Electron Transport/genetics; Iron-Sulfur Proteins/deficiency; Isoenzymes/deficiency/genetics/physiology; Longevity/genetics; Mitochondria/*enzymology; Oxidative Stress/genetics; Paraquat/toxicity; Promoter Regions, Genetic; *RNA Interference; Reactive Oxygen Species/metabolism; Saccharomyces cerevisiae Proteins/genetics; Superoxide Dismutase/*deficiency/genetics/physiology; Transcription Factors/genetics; Transgenes
Journal: Proceedings of the National Academy of Sciences of the United States of America
Volume: 99
Issue: 25
Pages: 16162-7
Date: Nov. 29, 2002
PMID: 12456885
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Citation:

Kirby K, Hu J, Hilliker AJ, Phillips JP (2002) RNA interference-mediated silencing of Sod2 in Drosophila leads to early adult-onset mortality and elevated endogenous oxidative stress. Proceedings of the National Academy of Sciences of the United States of America 99: 16162-7.


Study Lifespan Factors:
  • Sod2 Superoxide dismutase 2 (Mn)


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