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Hypersensitivity to oxygen and shortened lifespan in a Drosophila mitochondrial complex II mutant

Walker, David W. and Hájek, Petr and Muffat, Julien and Knoepfle, Dan and Cornelison, Stephanie and Attardi, Giuseppe and Benzer, Seymour (2006) Hypersensitivity to oxygen and shortened lifespan in a Drosophila mitochondrial complex II mutant. Proceedings of the National Academy of Sciences of the United States of America, 103 (44). pp. 16382-16387. ISSN 0027-8424. PMCID PMC1618815.

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Oxidative stress is implicated as a major cause of aging and age-related diseases, such as Parkinson's and Alzheimer's, as well as ischemia-reperfusion injury in stroke. The mitochondrial electron transport chain is the principal source of reactive oxygen species within cells. Despite considerable medical interest, the molecular mechanisms that regulate reactive oxygen species formation within the mitochondrion remain poorly understood. Here, we report the isolation and characterization of a Drosophila mutant with a defect in subunit b of succinate dehydrogenase (SDH; mitochondrial complex II). The sdhB mutant is hypersensitive to oxygen and displays hallmarks of a progeroid syndrome, including early-onset mortality and age-related behavioral decay. Pathological analysis of the flight muscle, which is amongst the most highly energetic tissues in the animal kingdom, reveals structural abnormalities in the mitochondria. Biochemical analysis shows that, in the mutant, there is a complex II-specific respiratory defect and impaired complex II-mediated electron transport, although the other respiratory complexes remain functionally intact. The complex II defect is associated with an increased level of mitochondrial hydrogen peroxide production, suggesting a possible mechanism for the observed sensitivity to elevated oxygen concentration and the decreased lifespan of the mutant fly.

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Additional Information:© 2006 by the National Academy of Sciences Contributed by Seymour Benzer, September 9, 2006. Published online before print October 20, 2006 We thank Rosalind Young for expert electron microscopy, members of the Bruce Hay laboratory for the use of their fluorometer, William Ja for advice and help with spectrophotometer-based assays, and George Martin of the University of Washington as well as members of the Benzer and Attardi laboratories for helpful discussions. This work was funded by grants from the Ellison Medical Foundation and National Institutes of Health (to S.B. and G.A.) and the National Science Foundation (to S.B.). Author contributions: D.W.W., P.H., J.M., D.K., S.C., G.A., and S.B. designed research; D.W.W., P.H., J.M., D.K., and S.C. performed research; D.W.W., P.H., J.M., D.K., S.C., G.A., and S.B. analyzed data; and D.W.W. and S.B. wrote the paper. The authors declare no conflict of interest. Freely available online through the PNAS open access option.
Funding AgencyGrant Number
Ellison Medical FoundationUNSPECIFIED
Subject Keywords:aging; hyperoxia; reactive oxygen species; sdhB; succinate dehydrogenase
Issue or Number:44
PubMed Central ID:PMC1618815
Record Number:CaltechAUTHORS:WALpnas06
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5557
Deposited By: Archive Administrator
Deposited On:25 Oct 2006
Last Modified:02 Oct 2019 23:24

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