HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: fj.05-5709comv1 21/2/333    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Llorens, J. V. Articles by Moltó, M. D. Search for Related Content PubMed PubMed Citation Articles by Llorens, J. V. Articles by Moltó, M. D.

Causative role of oxidative stress in a Drosophila model of Friedreich ataxia

José V. Llorens^*,1, Juan A. Navarro^*,,1, Maria J. Martínez-Sebastián^*, Mary K. Baylies, S. Schneuwly, José A. Botella and Maria D. Moltó^*,2

^* Departament de Genètica, Universitat de València, Burjassot, Valencia, Spain;

Institute of Zoology, University of Regensburg, Regensburg, Germany; and

Developmental Biology Program, Memorial Sloan Kettering Cancer Institute, New York, New York, USA

²Correspondence: Departament de Genètica, Facultat de Ciències Biològiques, Universitat de València, Carrer Doctor Moliner 50, 46100-Burjassot, Valencia, Spain. E-mail: dmolto{at}uv.es

Friedreich ataxia (FA), the most common form of hereditary ataxia, is caused by a deficit in the mitochondrial protein frataxin. While several hypotheses have been suggested, frataxin function is not well understood. Oxidative stress has been suggested to play a role in the pathophysiology of FA, but this view has been recently questioned, and its link to frataxin is unclear. Here, we report the use of RNA interference (RNAi) to suppress the Drosophila frataxin gene (fh) expression. This model system parallels the situation in FA patients, namely a moderate systemic reduction of frataxin levels compatible with normal embryonic development. Under these conditions, fh-RNAi flies showed a shortened life span, reduced climbing abilities, and enhanced sensitivity to oxidative stress. Under hyperoxia, fh-RNAi flies also showed a dramatic reduction of aconitase activity that seriously impairs the mitochondrial respiration while the activities of succinate dehydrogenase, respiratory complex I and II, and indirectly complex III and IV are normal. Remarkably, frataxin overexpression also induced the oxidative-mediated inactivation of mitochondrial aconitase. This work demonstrates, for the first time, the essential function of frataxin in protecting aconitase from oxidative stress-dependent inactivation in a multicellular organism. Moreover our data support an important role of oxidative stress in the progression of FA and suggest a tissue-dependent sensitivity to frataxin imbalance. We propose that in FA, the oxidative mediated inactivation of aconitase, which occurs normally during the aging process, is enhanced due to the lack of frataxin.—Llorens, J. V., Navarro, J. A., Martínez-Sebastián, M. J., Baylies, M. K., Schneuwly, S., Botella, J. A., Moltó, M. D. Causative role of oxidative stress in a Drosophila model of Friedreich ataxia.

Key Words: frataxin • aconitase • mitochondrial respiration • hyperoxia • RNAi

This article has been cited by other articles:

				J. Gardiner, D. Barton, R. Overall, and J. Marc Neurotrophic Support and Oxidative Stress: Converging Effects in the Normal and Diseased Nervous System Neuroscientist, February 1, 2009; 15(1): 47 - 61. [Abstract] [PDF]

				P. R. Anderson, K. Kirby, W. C. Orr, A. J. Hilliker, and J. P. Phillips Hydrogen peroxide scavenging rescues frataxin deficiency in a Drosophila model of Friedreich's ataxia PNAS, January 15, 2008; 105(2): 611 - 616. [Abstract] [Full Text] [PDF]