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Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions
C T Moraes1, E Ricci, V Petruzzella
1H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Disorders, New York, New York.
Abstract:
Large-scale deletions of mitochondrial DNA (mtDNA) are associated with a subgroup of mitochondrial encephalomyopathies. We studied seven patients with Kearns-Sayre syndrome or isolated ocular myopathy who harboured a sub-population of partially-deleted mitochondrial genomes in skeletal muscle. Variable cytochrome c oxidase (COX) deficiencies and reduction of mitochondrially-encoded polypeptides were found in affected muscle fibres, but while many COX-deficient fibres had increased levels of mutant mtDNA, they almost invariably had reduced levels of normal mtDNA. Our results suggest that a specific ratio between mutant and wild-type mitochondrial genomes is the most important determinant of a focal respiratory chain deficiency, even though absolute copy numbers may vary widely.
Insights
Large-scale mitochondrial DNA deletions cause mitochondrial encephalomyopathies. A specific ratio of mutant to normal mitochondrial genomes, not just copy number, determines respiratory chain deficiency in affected muscle fibers.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Large-scale mitochondrial DNA (mtDNA) deletions are linked to mitochondrial encephalomyopathies.
- Kearns-Sayre syndrome and isolated ocular myopathy are characterized by these deletions.
Purpose of the Study:
- To investigate the relationship between mutant mtDNA levels and respiratory chain function in patients with large-scale mtDNA deletions.
- To determine the key factors influencing cytochrome c oxidase (COX) deficiency in affected muscle.
Main Methods:
- Studied seven patients with Kearns-Sayre syndrome or isolated ocular myopathy.
- Analyzed skeletal muscle for subpopulations of partially deleted mitochondrial genomes.
- Assessed cytochrome c oxidase (COX) activity and levels of mitochondrially-encoded polypeptides in muscle fibers.
Main Results:
- Found variable COX deficiencies and reduced mitochondrially-encoded polypeptides in affected muscle fibers.
- Observed increased mutant mtDNA levels in many COX-deficient fibers.
- Noted that reduced levels of normal mtDNA, rather than absolute mutant mtDNA copy number, correlated with deficiency.
Conclusions:
- A specific ratio between mutant and wild-type mitochondrial genomes is the primary determinant of focal respiratory chain deficiency.
- This ratio is more critical than absolute copy numbers in predicting the severity of COX deficiency.