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Human Molecular Genetics Advance Access originally published online on October 3, 2005
Human Molecular Genetics 2005 14(22):3397-3405; doi:10.1093/hmg/ddi367
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© The Author 2005. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oxfordjournals.org

RNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila

Peter R. Anderson1, Kim Kirby1, Arthur J. Hilliker2 and John P. Phillips1,*

1Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada N1G 2W1 and 2Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3

* To whom correspondence should be addressed. Tel: +1 5198244120 ext. 52796; Fax: +1 5198372075; Email: jphillip{at}uoguelph.ca

Received August 4, 2005; Accepted September 27, 2005

The mitochondrial iron chaperone, frataxin, plays a critical role in cellular iron homeostasis and the synthesis and regeneration of Fe–S centers. Genetic insufficiency for frataxin is associated with Friedreich's Ataxia in humans and confers loss of function of Fe-containing proteins including components of the respiratory chain and mitochondrial and cytosolic aconitases. Here, we report the use of RNA-interference (RNAi) to suppress frataxin in the multicellular eukaryote, Drosophila. Phenotypically, suppression of the Drosophila frataxin homologue (dfh) confers distinct phenotypes in larvae and adults, leading to giant long-lived larvae and to conditional short-lived adults. Deficiency of the DFH protein results in diminished activities of numerous heme- and iron–sulfur-containing enzymes, loss of intracellular iron homeostasis and increased susceptibility to iron toxicity. In parallel with the differential larval and adult phenotypes, our results indicate that dfh silencing differentially dysregulates ferritin expression in adults but not in larvae. Moreover, silencing of dfh in the peripheral nervous system, a specific focus of Friedreich's pathology, permits normal larval development but imposes a marked reduction in adult lifespan. In contrast, dfh silencing in motorneurons has no deleterious effect in either larvae or adults. Finally, overexpression of Sod1, Sod2 or Cat does not suppress the failure of DFH-deficient animals to successfully complete eclosion, suggesting a minimal role of oxidative stress in this phenotype. The robust developmental, biochemical and tissue-specific phenotypes conferred by DFH deficiency in Drosophila provide a platform for identifying genetic, nutritional and environmental factors, which ameliorate the symptoms arising from frataxin deficiency.


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