title: Frataxin deficiency causes upregulation of mitochondrial Lon and ClpP proteases and severe loss of mitochondrial Fe-S proteins.
abstract: Friedreich ataxia (FRDA) is a rare hereditary neurodegenerative disease characterized by progressive ataxia and cardiomyopathy. The cause of the disease is a defect in mitochondrial frataxin, an iron chaperone involved in the maturation of Fe-S cluster proteins. Several human diseases, including cardiomyopathies, have been found to result from deficiencies in the activity of specific proteases, which have important roles in protein turnover and in the removal of damaged or unneeded protein. In this study, using the muscle creatine kinase mouse heart model for FRDA, we show a clear progressive increase in protein levels of two important mitochondrial ATP-dependent proteases, Lon and ClpP, in the hearts of muscle creatine kinase mutants. These proteases have been shown to degrade unfolded and damaged proteins in the matrix of mitochondria. Their upregulation, which was triggered at a mid-stage of the disease through separate pathways, was accompanied by an increase in proteolytic activity. We also demonstrate a simultaneous and significant progressive loss of mitochondrial Fe-S proteins with no substantial change in their mRNA level. The correlative effect of Lon and ClpP upregulation on loss of mitochondrial Fe-S proteins during the progression of the disease may suggest that Fe-S proteins are potential targets of Lon and ClpP proteases in FRDA.
authors.affiliation: Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France.
authors.forename: Blanche
authors.initials: B
authors.lastname: Guillon
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Bulteau
authors.forename: Marie
authors.initials: M
authors.lastname: Wattenhofer-Donzé
authors.forename: Stéphane
authors.initials: S
authors.lastname: Schmucker
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet
authors.forename: Hélène
authors.initials: H
authors.lastname: Puccio
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Drapier
authors.forename: Cécile
authors.initials: C
authors.lastname: Bouton
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D052283:Creatine Kinase, MM Form / Q000235:genetics / Q000502:physiology*; D049071:Endopeptidase Clp / Q000096:biosynthesis*; D005621:Friedreich Ataxia / Q000235:genetics / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics / Q000502:physiology*; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000502:physiology*; D009154:Mutation; D009206:Myocardium / Q000201:enzymology; D049070:Protease La / Q000096:biosynthesis*; D015854:Up-Regulation; D000096923:Frataxin
chemical_list: D000255:Adenosine Triphosphate; D052283:Creatine Kinase, MM Form; D049071:Endopeptidase Clp; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D049070:Protease La; D000096923:Frataxin