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Human Molecular Genetics Advance Access originally published online on March 17, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 10 1017-1024
DOI: 10.1093/hmg/ddh114
Human Molecular Genetics, Vol. 13, No. 10 © Oxford University Press 2004; all rights reserved

Idebenone delays the onset of cardiac functional alteration without correction of Fe-S enzymes deficit in a mouse model for Friedreich ataxia

Hervé Seznec1, Delphine Simon1, Laurent Monassier2, Paola Criqui-Filipe1, Anne Gansmuller1, Pierre Rustin3, Michel Koenig1 and Hélène Puccio1,*

1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch cedex, CU de Strasbourg, France, 2Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, INSERM E333, Faculté de Médecine, 67085 Strasbourg cedex, France and 3Unité de Recherche sur les Handicaps Génétiques de l'Enfant, INSERM U393, Hôpital Necker-Enfants Malades, 75015 Paris, France

Received January 8, 2004; Revised February 27, 2004; Accepted March 10, 2004

Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associated with cardiomyopathy, is caused by severely reduced frataxin, a mitochondrial protein involved in Fe-S cluster assembly. We have recently generated mouse models that reproduce important progressive pathological and biochemical features of the human disease. Our frataxin-deficient mouse models initially demonstrate time-dependent intramitochondrial iron accumulation, which occurs after onset of the pathology and after inactivation of the Fe-S dependent enzymes. Here, we report a more detailed pathophysiological characterization of our mouse model with isolated cardiac disease by echocardiographic, biochemical and histological studies and its use for placebo-controlled therapeutic trial with Idebenone. The Fe-S enzyme deficiency occurs at 4 weeks of age, prior to cardiac dilatation and concomitant development of left ventricular hypertrophy, while the mitochondrial iron accumulation occurs at a terminal stage. From 7 weeks onward, Fe-S enzyme activities are strongly decreased and are associated with lower levels of oxidative stress markers, as a consequence of reduced respiratory chain activity. Furthermore, we demonstrate that the antioxidant Idebenone delays the cardiac disease onset, progression and death of frataxin deficient animals by 1 week, but does not correct the Fe-S enzyme deficiency. Our results support the view that frataxin is a necessary, albeit non-essential, component of the Fe-S cluster biogenesis, and indicate that Idebenone acts downstream of the primary Fe-S enzyme deficit. Furthermore, our results demonstrate that Idebenone is cardioprotective even in the context of a complete lack of frataxin, which further supports its utilization for the treatment of FRDA.

* To whom correspondence should be addressed at: IGBMC, 1 rue Laurent Fries BP 10142, 67404 Illkirch, France. Tel: +33 388653433; Fax: +33 388653246; Email: hpuccio{at}igbmc.u-strasbg.fr


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