The point mutation of mitochondrial DNA characteristic for MERRF disease is found also in healthy people of different ages

Münscher, C.; Rieger, T.; Müller‐Höcker, Josef; Kadenbach, Bernhard

doi:10.1016/0014-5793(93)81484-h

Cited by 136 publications

(51 citation statements)

References 25 publications

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“…Many studies have focused on the levels of specific point mutations found previously in cases of mtDNA disease, such as A3243G (Liu et al ., 1998) or A8344G (Münscher et al ., 1993). Some of these mutations have been previously suggested to lie in mutational hotspot regions.…”

Section: Mtdna Point Mutations and Agingmentioning

confidence: 99%

The mitochondrial theory of aging: dead or alive?

Jacobs

2003

Aging Cell

108

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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.

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Section: Mtdna Point Mutations and Agingmentioning

confidence: 99%

The mitochondrial theory of aging: dead or alive?

Jacobs

2003

Aging Cell

108

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“…A-G; nt 4317, tRNA Ile , A-G; nt 5692, tRNA Asn , A-G; nt 8344, tRNA Lys , G-A; nt 10006, tRNA Gly , A-G; and 12246, tRNA Ser , A-G, Preparation of mtDNA Probes by point mutation specific PCR as previously described 30,31,59 on 18 microdissected probes of 6 formalin-fixed paraffin-embedded livers Specific probes of mtDNA (G1, G2, G3, Fig. 1) were produced by polymerase chain reaction (PCR) for in situ hybridization.…”

Section: In Situ Hybridizationmentioning

confidence: 99%

“…tions and more than 40 point mutations of mtDNA have been identified, 118,147,148 which may even coexist 30,31,149 the In situ hybridization and PCR studies in skeletal muscle have revealed that the mutated mtDNA molecules accumu-involvement of other mutations of mtDNA needs further elucidation. late in the respiratory deficient cells, [56][57][58] causing the enzyme defect when a certain threshold of mutated DNA is In summary the results show that defects of the respiratory chain represent a general phenomenon affecting not only reached.…”

Section: Aidmentioning

confidence: 99%

“…[19][20][21][22] Similar mutations also accumulate with age although at a lesser degree both in huhad defects and approximately 60% occurred after age 50. The defects were caused by a loss of enzyme protein involving mans [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] and in animals. [39][40][41][42][43][44][45][46][47] The present study reports on a random defect pattern of the respiratory chain in normal and both nuclearly and mitochondrially coded subunits.…”

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confidence: 99%

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Defects of the respiratory chain in the normal human liver and in cirrhosis during aging

et al. 1997

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cal studies of the respiratory chain complexes in these and Defects of the respiratory chain are a typical feature of mitochondrial diseases and occur also during normal aging other tissues [11][12][13][14][15][16][17] have revealed that aging is an inhomogeneous process at the cellular level leading to randomly diswhere they have been described in postmitotic tissues. The present study addresses the question of defect expression in tributed defects of cytochrome-c-oxidase (complex IV of the respiratory chain) and to intercellular and interorgan differthe normal and cirrhotic liver. Randomly distributed defects of complex III (ubiquinone-cytochrome-c-oxidoreductase) and ences of the defect manifestation.Recently a decline of respiratory rates with age was also of complex IV (cytochrome-c-oxidase) of the respiratory chain have been detected with age-related increasing frequency both reported for the human liver 18 both for unstimulated (state 4) and adenosine diphosphate-stimulated respiration (state in normal and cirrhotic livers. No defects were present for complex II (succinate-dehydrogenase) and complex V (adeno-3). In the last few years molecular genetic studies have revealed that mutations of mitochondrial DNA (mtDNA) such sine triphosphate-synthase) and in liver cell carcinomas. Sixty-one of 107 normal livers (57%) showed defects of the as deletions, duplications, point mutations in transfer RNAs (tRNAs), and structural genes are involved in the pathogenerespiratory chain. The defects occurred in advanced age (over 50 years) in 87%. In contrast 50 of 64 cirrhotic livers (78%) sis of mitochondrial diseases. [19][20][21][22] Similar mutations also accumulate with age although at a lesser degree both in huhad defects and approximately 60% occurred after age 50. The defects were caused by a loss of enzyme protein involving mans 23-38 and in animals. [39][40][41][42][43][44][45][46][47] The present study reports on a random defect pattern of the respiratory chain in normal and both nuclearly and mitochondrially coded subunits. Ninetyfour percent of the defects (n Å 275) involved complex IV cirrhotic livers during aging underlining that aging occurs primarily at the individual cellular level and that similar selectively. In 4% selective defects of complex III were found and combined defects of both complexes occurred in only pathogenetic mechanisms are involved in postmitotic fixed muscular tissue and in liver. Although the random defect 2%. In situ hybridization and polymerase chain reaction (PCR) studies for the detection of the common deletion (4.977 bp) pattern favors a stochastic process, molecular genetic analyses failed to reveal a pathogenetic role of various mutations and of various point mutations of mitochondrial DNA (mtDNA) revealed no consistent molecular genetic abnormali-of mtDNA. Loss of respiratory chain function is a typical feature of normal livers and to the 8th decade in patients with cirrhosis. The mitochondrial diseases. 1-3 To a lesser degree respiratory chain tissue probes were stored fr...

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“…Persistence of this damage would be expected to cause a high mutation rate in mtDNA. Thus, it is not surprising that mutations, including deletions, duplications, and point mutations, have been found to accumulate in mtDNA in a variety of tissues during aging in humans, monkeys, and rodents (68)(69)(70)(71)(72)(73) and cause a mosaic pattern of respiratory chain deficiency in pre-and post-mitotic tissues. The most frequent and best characterized age-associated mtDNA mutation is a 4977-bp deletion also called the "common deletion".…”

Section: Mitochondrial Dna Repair and Agingmentioning

confidence: 99%