Deletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in
E A Shoubridge1, G Karpati, K E Hastings
1Department of Neurology and Neurosurgery, Montreal Neurological Institute, Quebec, Canada.
Abstract:
We mapped the distribution and expression of wild-type and deleted mitochondrial DNA (mtDNA) molecules in skeletal muscle fibers of patients with mitochondrial disease. We show that ragged red fiber segments, which are characteristic histological features of these myopathies, represent focal accumulations of mitochondria containing predominantly deleted mtDNAs and that the mutant genomes are absent or extremely rare in normal fiber segments. This suggests that the mtDNA mutations play a direct role in focal mitochondrial accumulation. Although levels of wild-type mtDNAs and mRNAs in ragged red fiber segments are near normal, mitochondrial function, as revealed by cytochrome oxidase cytochemistry, is severely impaired. This suggests that the presence of mutant mtDNAs interferes with the expression of coexisting wild-type mtDNAs in these segments at a posttranscriptional level.
Insights
Mitochondrial DNA (mtDNA) deletions accumulate in specific muscle fiber segments in mitochondrial disease, causing impaired function. These mutations appear to disrupt the expression of normal mtDNA within these affected areas.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Mitochondrial myopathies are characterized by histological features like ragged red fibers.
- The role of mitochondrial DNA (mtDNA) mutations in the pathogenesis of these conditions is under investigation.
Purpose of the Study:
- To investigate the distribution and expression of wild-type and deleted mtDNA in skeletal muscle fibers of patients with mitochondrial disease.
- To determine the relationship between mtDNA mutations and the formation of ragged red fibers.
- To elucidate the mechanism by which mutant mtDNA affects mitochondrial function.
Main Methods:
- Mapping of wild-type and deleted mtDNA distribution and expression in skeletal muscle fibers.
- Histological analysis of ragged red fiber segments.
- Assessment of mitochondrial function using cytochrome oxidase cytochemistry.
Main Results:
- Ragged red fiber segments show focal accumulations of mitochondria with predominantly deleted mtDNAs.
- Mutant mtDNA genomes are rare in normal muscle fiber segments.
- Despite near-normal levels of wild-type mtDNA and mRNA in ragged red fibers, mitochondrial function is severely impaired.
Conclusions:
- mtDNA mutations play a direct role in the focal accumulation of mitochondria observed in ragged red fibers.
- The presence of mutant mtDNA interferes with the expression of coexisting wild-type mtDNA at a posttranscriptional level, leading to impaired mitochondrial function.
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