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The mitochondrial DNA A3243G mutation causes neuromuscular disease. To investigate the muscle-specific pathophysiology of mitochondrial disease, rhabdomyosarcoma transmitochondrial hybrid cells (cybrids) were generated that retain the capacity to differentiate to myotubes. In some cases, striated muscle-like fibres were formed after innervation with rat embryonic spinal cord. Myotubes carrying A3243G mtDNA produced more reactive oxygen species than controls, and had altered glutathione homeostasis. Moreover, A3243G mutant myotubes showed evidence of abnormal mitochondrial distribution, which was associated with down-regulation of three genes involved in mitochondrial morphology, Mfn1, Mfn2 and DRP1. Electron microscopy revealed mitochondria with ultrastructural abnormalities and paracrystalline inclusions. All these features were ameliorated by anti-oxidant treatment, with the exception of the paracrystalline inclusions. These data suggest that rhabdomyosarcoma cybrids are a valid cellular model for studying muscle-specific features of mitochondrial disease and that excess reactive oxygen species production is a significant contributor to mitochondrial dysfunction, which is amenable to anti-oxidant therapy.

Original publication

DOI

10.1093/brain/awm151

Type

Journal article

Journal

Brain

Publication Date

10/2007

Volume

130

Pages

2715 - 2724

Keywords

Adult, Animals, Antioxidants, Cell Differentiation, Cells, Cultured, DNA, Mitochondrial, Gene Expression Regulation, Humans, Male, Microscopy, Electron, Mitochondria, Muscle, Mitochondrial Myopathies, Muscle Cells, Muscle Fibers, Skeletal, Oxidation-Reduction, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species, Tumor Cells, Cultured