The age-related accumulation of a mitochondrial DNA control region mutation in muscle, but not brain, detected by a sensitive PNA-directed PCR clamping based method

Murdock, Deborah G.; Christacos, Nicole C.; Wallace, Douglas C.

doi:10.1093/nar/28.21.4350

Cited by 103 publications

(61 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The A189G transition has been previously described as polymorphisms (12). However, in the present work, none of the 54 muscle samples analyzed carried this mutation as a polymorphism.…”

Section: Discussioncontrasting

confidence: 46%

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

Wang

Michikawa

Mallidis

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

252

150

View full text Add to dashboard Cite

The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects <40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations. R ecently, the discovery of an aging-dependent large accumulation of point mutations in the control region for mtDNA replication of human skin fibroblasts has been reported (1). Particularly striking was the demonstration, in a generally high proportion of molecules (up to 50%), of a T to G transversion at position 414 in the original Cambridge sequence (2), within the promoter for the synthesis of the RNA primer of mtDNA heavy (H)-strand synthesis (3) and for light (L)-strand transcription (4). This mutation was present in more than 50% of the individuals above 65 years of age and absent in younger individuals. In the present work, to investigate the occurrence of these aging-dependent mutations in other cell types, in particular, in postmitotic cells, a screening was carried out for the detection in human muscle of aging-related specific point mutations in the DLP4 and DLP6 segments of the main mtDNA control region, which were the segments previously found to carry the fibroblast mtDNA mutations (1). These two mtDNA segments correspond to one of the hypervariable portions of the main control region (5), and were chosen, for the purpose of analysis, as containing each a uniform melting domain (Y.M., unpublished data). They carry critical sequences for mtDNA replication (Fig. 1A). In particular, DLP4 contains the primary origin of H-strand mtDNA synthesis (O H1 ) (3), whereas DLP6 contains the promoter and start site for H-strand replication RNA...

show abstract

“…The A189G transition has been previously described as polymorphisms (12). However, in the present work, none of the 54 muscle samples analyzed carried this mutation as a polymorphism.…”

Section: Discussioncontrasting

confidence: 46%

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

Wang

Michikawa

Mallidis

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

252

150

View full text Add to dashboard Cite

show abstract

“…Nevertheless, they have been found to accumulate, at least at the whole tissue level, to truly minute levels, never more than a tiny fraction of a per cent of total mtDNA, except in individuals who are members of already recognized families with mtDNA disease. In fact, despite earlier reports which claimed to detect these mutations rather commonly, in various tissues of aged subjects (Münscher et al ., 1993;Liu et al ., 1998), a recent study, using a reliable, sensitive and quantitative method, failed to find the A3243G or A8344G mutations in brain or muscle of aged subjects, above the detection limit of 0.1% (Murdock et al ., 2000).…”

Section: Mtdna Point Mutations and Agingmentioning

confidence: 99%

The mitochondrial theory of aging: dead or alive?

Jacobs

2003

Aging Cell

106

View full text Add to dashboard Cite

The mitochondrial theory of aging is based around the idea of a vicious cycle, in which somatic mutation of mtDNA engenders respiratory chain dysfunction, enhancing the production of DNA-damaging oxygen radicals. In turn, this is proposed to result in the accumulation of further mtDNA mutations. Finally, a bioenergetic crisis leads to overt tissue dysfunction and degeneration. A substantial body of circumstantial evidence seems to support this idea. However, the extent of detectable mtDNA mutation is far less than can easily be reconciled to this hypothesis, unless it is assumed that a subset of cells with much higher than average mtDNA mutation load is systematically lost by apoptosis. A rigorous test of the hypothesis remains to be undertaken, but would require a direct manipulation of the rate of mtDNA mutagenesis, to test whether this could alter the kinetics of aging.

show abstract

“…This transition presents high, easily detectable heteroplasmic mutation rates in muscle tissue. Its level been detected at an increasing rate in muscle tissue from older individuals [4,5,7,8,9].…”

Section: Introductionmentioning

confidence: 99%

Detection of the A189G mtDNA heteroplasmic mutation in relation to age in modern and ancient bones

Lacan

Thèves

Amory³

et al. 2008

Int J Legal Med

View full text Add to dashboard Cite

Abstract:The aim of this study was to demonstrate the presence of the A189G age-related point mutation on DNA extracted from bone. For this, a PNA/DNA sequencing method which can determine an age threshold for the appearance of the mutation was used.Initially, work was done in muscle tissue in order to evaluate the sensitivity of the technique and afterwards in bone samples from the same individuals. This method was also applied to ancient bones from 6 well preserved skeletal remains. The mutation was invariably found in muscle, and at a rate of up to 20% in individuals over 60 years old.In modern bones, the mutation was detected in individuals aged 38 years old or more, at a rate of up to 1%, but its occurrence was not systematic (only 4 out of 10 of the individuals over 50 years old carried the heteroplasmy). For ancient bones, the mutation was also found in the oldest individuals according to osteologic markers. The study of this type of age-related mutation and a more complete understanding of its manifestation has potentially useful applications. Combined with traditional age markers, it could improve identification accuracy in forensic cases or in anthropological studies of ancient populations.

show abstract

The age-related accumulation of a mitochondrial DNA control region mutation in muscle, but not brain, detected by a sensitive PNA-directed PCR clamping based method

Cited by 103 publications

References 33 publications

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

The mitochondrial theory of aging: dead or alive?

Detection of the A189G mtDNA heteroplasmic mutation in relation to age in modern and ancient bones

Contact Info

Product

Resources

About