Frataxin deficiency causes upregulation of mitochondrial Lon and ClpP proteases and severe loss of mitochondrial Fe-S proteins.
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.
Guillon
Blanche
B
Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France.
Bulteau
Anne-Laure
AL
Wattenhofer-Donzé
Marie
M
Schmucker
Stéphane
S
Friguet
Bertrand
B
Puccio
Hélène
H
Drapier
Jean-Claude
JC
Bouton
Cécile
C
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
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