title: Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia.
abstract: Friedreich's ataxia (FRDA) is an autosomal recessive disorder, caused by reduced levels of the protein frataxin. This protein is located in the mitochondria, where it functions in the biogenesis of iron-sulphur clusters (ISCs), which are important for the function of the mitochondrial respiratory chain complexes. Moreover, disruption in iron biogenesis may lead to oxidative stress. Oxidative stress can be the cause and/or the consequence of mitochondrial energy imbalance, leading to cell death. Fibroblasts from two FRDA mouse models, YG8R and KIKO, were used to analyse two different categories of protective compounds: deuterised poly-unsaturated fatty acids (dPUFAs) and Nrf2-inducers. The former have been shown to protect the cell from damage induced by lipid peroxidation and the latter trigger the well-known Nrf2 antioxidant pathway. Our results show that the sensitivity to oxidative stress of YG8R and KIKO mouse fibroblasts, resulting in cell death and lipid peroxidation, can be prevented by d4-PUFA and Nrf2-inducers (SFN and TBE-31). The mitochondrial membrane potential (ΔΨm) of YG8R and KIKO fibroblasts revealed a difference in their mitochondrial pathophysiology, which may be due to the different genetic basis of the two models. This suggests that variable levels of reduced frataxin may act differently on mitochondrial pathophysiology and that these two cell models could be useful in recapitulating the observed differences in the FRDA phenotype. This may reflect a different modulatory effect towards cell death that will need to be investigated further.
authors.affiliation: Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, WC1N 3BG London, UK.
authors.forename: Rosella
authors.initials: R
authors.lastname: Abeti
authors.affiliation: Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, WC1N 3BG London, UK.
authors.forename: Ebru
authors.initials: E
authors.lastname: Uzun
authors.affiliation: Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, WC1N 3BG London, UK.
authors.forename: Indhushri
authors.initials: I
authors.lastname: Renganathan
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
authors.affiliation: Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health & Life Sciences Synthetic Biology Theme, Institute of Environment, Health & Societies, Brunel University London, Uxbridge UB8 3PH, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pook
authors.affiliation: Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, WC1N 3BG London, UK. Electronic address: p.giunti@ucl.ac.uk.
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005621:Friedreich Ataxia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D010616:Phenanthrenes / Q000494:pharmacology; D010641:Phenotype; D000096923:Frataxin
chemical_list: D000975:Antioxidants; D007501:Iron; D033862:Iron-Binding Proteins; D010616:Phenanthrenes; D000096923:Frataxin; C531972:TBE 31
keywords: Friedreich's ataxia; Lipid peroxidation; Mitochondria; Nuclear factor E2 related factor; Oxidative stress; Poly-unsaturated fatty acids