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Role of mitochondrial DNA mutations in human aging: implications for the central nervous system and muscle
E J Brierley1, M A Johnson, R N Lightowlers
1Department of Neurology, The Medical School, University of Newcastle upon Tyne, UK.
Abstract:
It has been proposed that one mechanism for nerve and muscle dysfunction with age involves the mitochondria. Mitochondria contain the only DNA outside the nucleus in mammalian cells. Mitochondrial DNA (mtDNA) has a high mutation rate, and low levels of pathogenic mutations have been found in tissues from elderly subjects. However, the role of these mutations in the aging process is uncertain unless a mechanism can be identified that would lead to a biochemical defect. In muscle tissue from normal elderly subjects we show that there are muscle fibers with very low activity of cytochrome c oxidase, suggestive of a mtDNA defect. In these cytochrome c oxidase-deficient fibers we have found very high levels of mutant mtDNA. In addition, different mtDNA mutations are present in different fibers, which explains why there is a low overall incidence of an individual mutation in tissues from elderly subjects. These studies show a direct age-related correlation between a biochemical and genetic defect in normal human tissues and that mtDNA abnormalities are involved in the aging process in human muscle.
Insights
Aging muscle dysfunction may stem from mitochondrial DNA (mtDNA) mutations. Studies reveal age-related mtDNA defects correlate with biochemical deficits in human muscle fibers, implicating mtDNA in the aging process.
Area of Science:
- Mitochondrial biology
- Aging research
- Human genetics
Background:
- Mitochondria possess unique DNA (mtDNA) outside the nucleus, crucial for cellular energy production.
- mtDNA exhibits a high mutation rate, with low levels of mutations observed in elderly individuals.
- The direct link between mtDNA mutations and age-related cellular dysfunction remains unclear.
Purpose of the Study:
- To investigate the role of mitochondrial DNA (mtDNA) mutations in age-related nerve and muscle dysfunction.
- To establish a biochemical link between genetic defects in mtDNA and cellular function in aging muscle.
Main Methods:
- Analysis of muscle tissue from normal elderly subjects.
- Assay for cytochrome c oxidase activity in individual muscle fibers.
- Quantification of mutant mitochondrial DNA (mtDNA) levels in cytochrome c oxidase-deficient fibers.
Main Results:
- Identified muscle fibers with significantly reduced cytochrome c oxidase activity, indicating mtDNA defects.
- Detected very high levels of mutant mtDNA within these deficient muscle fibers.
- Observed distinct mtDNA mutations in different muscle fibers, explaining low overall mutation incidence.
Conclusions:
- Demonstrated a direct age-related correlation between biochemical and genetic defects in normal human muscle.
- Provided evidence that mitochondrial DNA (mtDNA) abnormalities contribute to the aging process in human muscle.
- Established a mechanism linking mtDNA mutations to cellular dysfunction during aging.