title: 'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'.
abstract: Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure.
authors.affiliation: Ataxia Centre, Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Abeti
authors.affiliation: Ataxia Centre, Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Parkinson
authors.affiliation: National Hospital, Neurometabolic Unit, London UK.
authors.forename: I P
authors.initials: IP
authors.lastname: Hargreaves
authors.affiliation: Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Angelova
authors.affiliation: Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health & Life Sciences, and Synthetic Biology Theme, Institute of Environment, Health & Societies, Brunel University London, Uxbridge, UK.
authors.forename: C
authors.initials: C
authors.lastname: Sandi
authors.affiliation: Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health & Life Sciences, and Synthetic Biology Theme, Institute of Environment, Health & Societies, Brunel University London, Uxbridge, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Pook
authors.affiliation: Ataxia Centre, Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Giunti
authors.affiliation: Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, UK.
authors.forename: A Y
authors.initials: AY
authors.lastname: Abramov
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D005621:Friedreich Ataxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000096923:Frataxin
chemical_list: D042967:Electron Transport Complex I; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III; D005978:Glutathione; D007501:Iron; D033862:Iron-Binding Proteins; D017382:Reactive Oxygen Species; D000096923:Frataxin