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: Nor Azian Abdul Murad, Jason K Cullen, Matthew McKenzie, Michael T Ryan, David Thorburn, Nuri Gueven, Junya Kobayashi, Geoff Birrell, Jian Yang, Thilo Dörk, Olivier Becherel, Padraic Grattan-Smith, Martin F Lavin
• Journal: Mitochondrion (Mitochondrion) Vol. 13 Issue 3 Pg. 235-45 (May 2013) ISSN: 1872-8278 [Electronic] Netherlands
• PMID: 23178371 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2012 Elsevier B.V. and Mitochondria Research Society. All rights reserved. Published by Elsevier B.V. All rights reserved.

Chemical References

• DNA, Mitochondrial
• Reactive Oxygen Species
• TP53 protein, human
• Tumor Suppressor Protein p53
• Cytochromes b

Topics

• Amino Acid Substitution
• Animals
• Ataxia (genetics, metabolism, pathology)
• Chromosome Disorders (genetics, metabolism, pathology)
• Cytochromes b (genetics, metabolism)
• DNA Mutational Analysis
• DNA, Mitochondrial (genetics, metabolism)
• Electron Transport (genetics)
• Humans
• Membrane Potential, Mitochondrial
• Mitochondria (genetics, metabolism, pathology)
• Mitochondrial Diseases (genetics, metabolism, pathology)
• Mutation, Missense
• Oxidative Stress (genetics)
• Protein Stability
• Reactive Oxygen Species (metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)