Identification of Ataxia-associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids

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DOIResolve DOI: http://doi.org/10.1002/mus.21355
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TypeArticle
Journal titleMuscle and Nerve
Volume40
Issue3
Pages381394; # of pages: 14
Subjectantioxidant; homoplasmic mutations; mitochondrial; oxidative stress; therapy
AbstractThe potential pathogenicity of two homoplasmic mtDNA point mutations, 9035T>C and 4452T>C, found in a family afflicted with maternally transmitted cognitive developmental delay, learning disability, and progressive ataxia was evaluated using transmitochondrial cybrids. We confirmed that the 4452T>C transition in tRNAMet represented a polymorphism; however, 9035T>C conversion in the ATP6 gene was responsible for a defective F₀-ATPase. Accordingly, mutant cybrids had a reduced oligomycin-sensitive ATP hydrolyzing activity. They had less than half of the steady-state content of ATP and nearly an 8-fold higher basal level of reactive oxygen species (ROS). Mutant cybrids were unable to cope with additional insults, i.e., glucose deprivation or tertiary-butyl hydroperoxide, and they succumbed to either apoptotic or necrotic cell death. Both of these outcomes were prevented by the antioxidants CoQ₁₀ and vitamin E, suggesting that the abnormally high levels of ROS were the triggers of cell death. In conclusion, the principal metabolic defects, i.e., energy deficiency and ROS burden, resulted from the 9035T>C mutation and could be responsible for the development of clinical symptoms in this family. Furthermore, antioxidant therapy might prove helpful in the management of this disease.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Biological Sciences
Peer reviewedYes
NPARC number15463950
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Record identifier66b3ae8e-98b0-4dbf-99d1-50f64daaed2c
Record created2010-08-16
Record modified2016-05-09
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