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BACKGROUND: Friedreich's ataxia (FRDA) is a mitochondrial rare disease, which molecular origin is associated with defect in the expression of frataxin. The pathological consequences are degeneration of nervous system structures and cardiomyopathy with necrosis and fibrosis, among others. PRINCIPAL FINDINGS: Using FRDA fibroblasts we have characterized the oxidative stress status and mitochondrial biogenesis. We observed deficiency of MnSOD, increased ROS levels and low levels of ATP. Expression of PGC-1α and mtTFA was increased and the active form of the upstream signals p38 MAPK and AMPK in fibroblasts from two patients. Interestingly, the expression of energetic factors correlated with the natural history of disease of the patients, the age when skin biopsy was performed and the size of the GAA expanded alleles. Furthermore, idebenone inhibit mitochondriogenic responses in FRDA cells. CONCLUSIONS: The induction of mitochondrial biogenesis in FRDA may be a consequence of the mitochondrial impairment associated with disease evolution. The increase of ROS and the involvement of the oxidative phosphorylation may be an early event in the cell pathophysiology of frataxin deficiency, whereas increase of mitochondriogenic response might be a later phenomenon associated to the individual age and natural history of the disease, being more evident as the patient age increases and disease evolves. This is a possible explanation of heart disease in FRDA.

Original publication

DOI

10.1371/journal.pone.0020666

Type

Journal article

Journal

PLoS One

Publication Date

2011

Volume

6

Keywords

AMP-Activated Protein Kinases, Adenosine Triphosphate, Adolescent, Adult, Aging, Alleles, Antioxidants, Catalase, Child, DNA-Binding Proteins, Disease Progression, Energy Metabolism, Female, Fibroblasts, Friedreich Ataxia, Gene Expression Regulation, Glutathione Peroxidase, Heat-Shock Proteins, Humans, Male, Middle Aged, Mitochondria, Mitochondrial Proteins, Oxidative Stress, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Reactive Oxygen Species, Signal Transduction, Superoxide Dismutase, Transcription Factors, Trinucleotide Repeats, Ubiquinone, p38 Mitogen-Activated Protein Kinases