Mitochondrial Dna Mutations as an Important Contributor to Ageing and Degenerative Diseases

Linnane, A. W.; Ozawa, Takayuki; Marzuki, Sangkot; Tanaka, Masashi

doi:10.1016/s0140-6736(89)92145-4

Cited by 1,124 publications

(561 citation statements)

References 25 publications

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“…It has been suggested that an accumulation of somatic DNA mutations with time may underlie the deleterious cellular changes that increase with age in mammals (1)(2)(3)(4)(5)(6). In the nuclear genome, inappropriate mutational inactivation of nuclear genes occurs with age (7), as well as inappropriate reactivation of silent genes (8)(9)(10).…”

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confidence: 99%

“…In the nuclear genome, inappropriate mutational inactivation of nuclear genes occurs with age (7), as well as inappropriate reactivation of silent genes (8)(9)(10). The accumulation of deleterious mutations in the mitochondrial genome has also been proposed to be important in aging (2)(3)(4)(5). It was known that some types of DNA damage occur at higher levels in mitochondrial DNA (mtDNA) and that mitochondria are deficient for some types of DNA repair; some repeated nuclear sequences also show such a deficiency (11)(12)(13)(14).…”

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confidence: 99%

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A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues.

Cortopassi

Shibata

Soong

et al. 1992

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

561

284

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An assay that selectively amplifes a specific deletion ofthe mitochondrial genome has been used to study the extent of the deletion's accumulation in a variety of human tissues. The deletion occurs at much higher levels in nervous and muscle tissues than in all other tissues studied. The variation in deletion level between the same tissues in different persons of similar age appears to be less than the variation among tissues within an individual. Tests for artifactual explanations of the level differences were each negative. Three cellular parameters that are correlated with the level of the deletion are identified. The preferential accumulation of deleterious mitochondrial mutations in a restricted subset of aging human tissues may compound deficiencies of function in those tissues that accrue with age.

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confidence: 99%

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confidence: 99%

A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues.

Cortopassi

Shibata

Soong

et al. 1992

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

561

284

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“…mtDNA somatic mutations lead to a decline in mitochondrial function, which contributes to ageing and degenerative diseases (Linnane et al, 1989;Wallace, 2005). The fate of heteroplasmic mutations depends on several factors, including the replication rate of the cell, type and location of the variation (DiMauro and Davidzon, 2005;Lacan et al, 2008).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

The link between mitochondrial DNA hypervariable segment I heteroplasmy and ageing among genetically unrelated Latvians

Pliss

Brakmanis

Ranka

et al. 2011

Experimental Gerontology

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To cite this version:This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractVarious studies have demonstrated that mitochondrial DNA (mtDNA) heteroplasmy tends to increase with age and that the observed frequency of heteroplasmy among populations mostly depends on the way it is measured. Therefore, we investigated age-related association on the presence of mtDNA heteroplasmy within the hypervariable segment 1 (HVS-I) in a selected study group. The study group consisted of 300 maternally unrelated Latvians ranging in age from 18 to over 90 years. To determine the optimal method for mtDNA heteroplasmy detection, three The results indicate that heteroplasmy in HVS-I is relatively common and occurs in a broad spectrum of sites. The above is supported by evidence to eventual increase of the probability of heteroplasmy with age due to specific mitochondrial haplogroup background. Research HighlightsThe results indicate that heteroplasmy in HVS-I is relatively common and occurs in a broad spectrum of sites. Consequently, a strong association is found to exist between the mtDNA heteroplasmy and ageing in the studied population.We found that the Denaturing Gradient Gel Electrophoresis (DGGE) and the SURVEYOR TM Mutation Detection Kit assay exhibited a lower limit of detection (LOD) of mtDNA heteroplasmy and revealed the presence of heteroplasmy at the already existing 1% and 5% occurrence in the sample.

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“…First discovered in patients suffering from mitochondrial myopathies, this deletion was later found to occur in all adult humans and to increase exponentially with age (71,72). The tissues that exhibit the highest levels of the mtDNA deletions are usually post-replicative and tend to have the highest metabolic rate (73)(74)(75)(76)(77).…”

Section: Relationship Between Deletions and Oxidative Damagementioning

confidence: 99%

Mitochondria, oxidative DNA damage, and aging

Anson

Bohr

2000

AGE

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Protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage is well known to be necessary to longevity. The relevance of mitochondrial DNA (mtDNA) to aging is suggested by the fact that the two most commonly measured forms of mtDNA damage, deletions and the oxidatively induced lesion 8-oxo-dG, increase with age. The rate of increase is species-specific and correlates with maximum lifespan.It is less clear that failure or inadequacies in the protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage are sufficient to explain senescence. DNA containing 8-oxo-dG is repaired by mitochondria, and the high ratio of mitochondrial to nuclear levels of 8-oxo-dG previously reported are now suspected to be due to methodological difficulties. Furthermore, MnSOD -/+ mice incur higher than wild type levels of oxidative damage, but do not display an aging phenotype. Together, these findings suggest that oxidative damage to mitochondria is lower than previously thought, and that higher levels can be tolerated without physiological consequence.A great deal of work remains before it will be known whether mitochondrial oxidative damage is a "clock" which controls the rate of aging. The increased level of 8-oxo-dG seen with age in isolated mitochondria needs explanation. It could be that a subset of cells lose the ability to protect or repair mitochondria, resulting in their incurring disproportionate levels of damage. Such an uneven distribution could exceed the reserve capacity of these cells and have serious physiological consequences.

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Mitochondrial Dna Mutations as an Important Contributor to Ageing and Degenerative Diseases

Cited by 1,124 publications

References 25 publications

A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues.

A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues.

The link between mitochondrial DNA hypervariable segment I heteroplasmy and ageing among genetically unrelated Latvians

Mitochondria, oxidative DNA damage, and aging

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