Human Molecular Genetics Advance Access published online on December 22, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi042
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1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch cedex, CU de Strasbourg, France
* To whom correspondence should be addressed. Friedreich ataxia (FRDA) results from a generalized deficiency of mitochondrial and cytosolic iron-sulfur protein activity initially ascribed to mitochondrial iron overload. Recent in vitro data suggest that frataxin is necessary for iron incorporation in [Fe-S] cluster (ISC) and heme biosynthesis. In addition, several reports suggest that continuous oxidative damage resulting from hampered superoxide dismutases (SODs) signaling participates in the mitochondrial deficiency and ultimately the neuronal and cardiac cell death. This has led to the use of antioxidants as idebenone for FRDA therapy. To further discern the role of oxidative stress in FRDA pathophysiology, we have tested the potential effect of increased antioxidant defense using an MnSOD mimetic (MnTBAP) and Cu,ZnSOD overexpression on the murine FRDA cardiomyopathy. Surprisingly, no positive effect was observed, suggesting that increased superoxide production could not explain by itself the FRDA cardiac pathophysiology. Moreover, we demonstrate that complete frataxin-deficiency does not induce oxidative stress in neuronal tissues nor alters the MnSOD expression and induction in the early step of the pathology (neuronal and cardiac) as previously suggested. We show that cytosolic ISC aconitase activity of IRP-1 progressively decreases while its apo-RNA binding form increases despite the absence of oxidative stress suggesting that in a mammalian system, the mitochondrial ISC assembly machinery is essential for cytosolic ISC biogenesis. In conclusion, our data demonstrate that in FRDA, mitochondrial iron accumulation does not induce oxidative stress and we propose that, contrary to the general assumption, FRDA is a neurodegenerative disease not associated with oxidative damage.
Article
Friedreich ataxia, the oxidative stress paradox
2 Institut de Chimie des Substances Naturelles (ICSN), CNRS, avenue de la Terrasse, 91190 Gif-sur-Yvette, France
3 Center for Molecular and Mitochondrial Medicine and Genetics (MAMMAG), University of California Irvine, Irvine, CA 92697, USA
4 Department of Pharmaceutical Sciences, 4200 East Ninth Avenue, Box C238. University of Colorado Health Sciences Center. Denver CO 80262
5 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/Université Louis Pasteur, 1 rue Laurent Fries BP 10142, 67404 Illkirch cedex, CU de Strasbourg, France
Hélène Puccio, E-mail: hpuccio{at}igbmc.u-strasbg.fr
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