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Mutations in the cardiac mitochondrial DNA control region associated with cardiomyopathy and aging
José Marín-García1, Oleg Zoubenko, Michael J Goldenthal
1Molecular Cardiology and Neuromuscular Institute, Highland Park, New Jersey 08904, USA.
Background:
An age-dependent accumulation of point mutations in the noncoding control region of human mitochondrial D-loop has been found in cultured fibroblasts and muscle cells. Damage in mitochondrial DNA (mtDNA) coding genes and decreased bioenergetic generation have also been found in human cardiac tissues with aging and in cardiac disease.
Methods And Results:
We analyzed cardiac mtDNA for the incidence and distribution of point mutations in the D-loop control region involved in mtDNA replication (from nucleotides 110 to 570) in 47 patients with cardiomyopathy and 40 subjects with no history of cardiac disease. The nucleotide changes in the control region were compared with changes in a cytb fragment of roughly the same size in controls and patients. Frequency and distribution of mutations in relation to age and cardiac disease were assessed. No significant accumulation of point mutations in the D-loop control region or in cytb was found as a function of age. However, mutations in important sites within the D-loop control region were present in 8 patients (17%).
Conclusions:
We found specific mutations at critical sites in the D-loop in cardiomyopathy that may play a role in cardiac pathogenesis. Age does not appear to be a factor in mutation accumulation.
Insights
Specific mutations in the mitochondrial DNA D-loop control region were found in cardiomyopathy patients, suggesting a role in heart disease pathogenesis. Age did not correlate with mutation accumulation in this study.
Area of Science:
- Genetics
- Cardiology
- Mitochondrial Biology
Background:
- Mitochondrial DNA (mtDNA) D-loop mutations accumulate with age in some cell types.
- Cardiac aging and disease are associated with mtDNA damage and reduced bioenergetics.
Purpose of the Study:
- To investigate the incidence and distribution of D-loop point mutations in cardiac mtDNA from cardiomyopathy patients and controls.
- To assess the relationship between these mutations, age, and cardiac disease.
Main Methods:
- Analysis of cardiac mtDNA D-loop control region (nucleotides 110-570) for point mutations in 47 cardiomyopathy patients and 40 controls.
- Comparison of mutation patterns with a cytb fragment of similar size.
- Assessment of mutation frequency and distribution relative to age and cardiac disease status.
Main Results:
- No significant age-dependent accumulation of point mutations was observed in the D-loop or cytb regions.
- Specific mutations within critical sites of the D-loop control region were identified in 17% (8/47) of cardiomyopathy patients.
Conclusions:
- Specific D-loop mutations in cardiomyopathy patients may contribute to cardiac pathogenesis.
- Age is not a significant factor in the accumulation of these specific D-loop mutations in the context of cardiac disease.