title: Mitochondrial dysfunction in a novel form of autosomal recessive ataxia.
abstract: Defects in the recognition and/or repair of damage to DNA are responsible for a sub-group of autosomal recessive ataxias. Included in this group is a novel form of ataxia with oculomotor apraxia characterised by sensitivity to DNA damaging agents, a defect in p53 stabilisation, oxidative stress and resistance to apoptosis. We provide evidence here that the defect in this patient's cells is at the level of the mitochondrion. Mitochondrial membrane potential was markedly reduced in cells from the patient and ROS levels were elevated. This was accompanied by lipid peroxidation of mitochondrial proteins involved in electron transport and RNA synthesis. However, no gross changes or alteration in composition or activity of mitochondrial electron transport complexes was evident. Sequencing of mitochondrial DNA revealed a mutation, I349T, in the mitochondrial cytochrome b gene. These results describe a patient with an apparently novel form of AOA characterised by a defect at the level of the mitochondrion.
authors.affiliation: Cancer and Cell Biology, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Nor Azian Abdul
authors.initials: NA
authors.lastname: Murad
authors.forename: Jason K
authors.initials: JK
authors.lastname: Cullen
authors.forename: Matthew
authors.initials: M
authors.lastname: McKenzie
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ryan
authors.forename: David
authors.initials: D
authors.lastname: Thorburn
authors.forename: Nuri
authors.initials: N
authors.lastname: Gueven
authors.forename: Junya
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Geoff
authors.initials: G
authors.lastname: Birrell
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.forename: Olivier
authors.initials: O
authors.lastname: Becherel
authors.forename: Padraic
authors.initials: P
authors.lastname: Grattan-Smith
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045303:Cytochromes b / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004579:Electron Transport / Q000235:genetics; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D018384:Oxidative Stress / Q000235:genetics; D055550:Protein Stability; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D045303:Cytochromes b