Cellular and molecular studies in muscle and cultures from patients with multiple mitochondrial DNA deletions
R Carrozzo1, M M Davidson, W F Walker
1H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Department of Neurology, College of Physicians and Surgeons of Columbia University, 630 W 168 Street, New York, NY 10032, USA.
Abstract:
In the last decade, several mitochondrial encephalomyopathies have been pathogenically associated with large-scale mitochondrial DNA deletions that are sporadic, or with point mutations that are maternally inherited. The mutations were also demonstrated in cultures of muscle satellite cells obtained from the patients. Subsequently, multiple deletions in mitochondrial DNA were found in several families. The affected members had progressive external ophthalmoplegia, cataracts and limb weakness, inherited as an autosomal dominant trait, or progressive external ophthalmoplegia with neurogastrointestinal encephalomyopathy or with cardiomyopathy, inherited as an autosomal recessive trait. To better understand the developmental pathobiology and localization of the multiple deletions, we performed comparative molecular genetic studies in muscle and cultures from patients. Whereas multiple deletions were found in muscle fragments from which muscle satellite cells were removed by enzymatic digestion, no deletions were found in the satellite cells or their cultured progeny. Our results suggest that multiple mitochondrial DNA deletions arise as somatic mutations during later stages of muscle development, or in terminally differentiated myofibers.
Insights
Multiple mitochondrial DNA deletions, linked to encephalomyopathies, appear to arise as somatic mutations in mature muscle cells, not inherited in satellite cells.
Area of Science:
- Molecular biology
- Genetics
- Neuroscience
Background:
- Mitochondrial encephalomyopathies are often linked to mitochondrial DNA (mtDNA) deletions or point mutations.
- These mutations can be sporadic or maternally inherited, and have been found in muscle satellite cells.
- Familial cases show varied inheritance patterns and clinical presentations, including ophthalmoplegia, cataracts, and myopathies.
Purpose of the Study:
- To investigate the developmental origin and cellular localization of multiple mtDNA deletions.
- To differentiate between inherited and somatically acquired mtDNA deletions in muscle tissues.
Main Methods:
- Comparative molecular genetic analysis of muscle fragments and cultured muscle satellite cells from patients.
- Enzymatic digestion to isolate muscle satellite cells from muscle tissue.
Main Results:
- Multiple mtDNA deletions were detected in muscle fragments after satellite cell removal.
- No mtDNA deletions were found in isolated muscle satellite cells or their cultured descendants.
- This indicates deletions are not present in the progenitor cells.
Conclusions:
- Multiple mtDNA deletions likely originate as somatic mutations.
- These mutations occur during later stages of muscle development or in terminally differentiated myofibers.
- This finding refines our understanding of the pathobiology of certain mitochondrial disorders.
