title: Idebenone delays the onset of cardiac functional alteration without correction of Fe-S enzymes deficit in a mouse model for Friedreich ataxia.
abstract: 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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, Illkirch, CU de Strasbourg, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Seznec
authors.forename: Delphine
authors.initials: D
authors.lastname: Simon
authors.forename: Laurent
authors.initials: L
authors.lastname: Monassier
authors.forename: Paola
authors.initials: P
authors.lastname: Criqui-Filipe
authors.forename: Anne
authors.initials: A
authors.lastname: Gansmuller
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
authors.forename: Hélène
authors.initials: H
authors.lastname: Puccio
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000627:therapeutic use*; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004562:Electrocardiography; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D033862:Iron-Binding Proteins / Q000235:genetics; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress; D014451:Ubiquinone / Q000031:analogs & derivatives; D000096923:Frataxin
chemical_list: D016227:Benzoquinones; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D014451:Ubiquinone; D000096923:Frataxin; C036619:idebenone