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

Cortopassi, Gino A; Shibata, Darryl; Soong, Nay-Wei; Arnheim, Norman

doi:10.1073/pnas.89.16.7370

Cited by 567 publications

(316 citation statements)

References 34 publications

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“…Conversely muscle seems to progressively increase with age its mutation load in patients with inherited mtDNA deletion [24] or point mutation [25]. Normal ageing is accompanied by the progressive accumulation of low proportions of mtDNA deletions and point mutations in post-mitotic tissues [26].…”

Section: Clinical Observationsmentioning

confidence: 99%

Unsolved issues related to human mitochondrial diseases

et al. 2014

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Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed.Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.

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Section: Clinical Observationsmentioning

confidence: 99%

Unsolved issues related to human mitochondrial diseases

et al. 2014

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“…Two different situations were investigated, one in-VOL. 14,1994 on The CAP' mutation was analyzed in the parental cell lines 143B and CAP23 and in 13 cybrids isolated in the first fusion experiment (time of analysis, 57 days after fusion) by PCR amplification of total cell DNA with a mismatched primer and by running the PCR products on a 5% polyacrylamide gel, as described in Materials and Methods. Indicated are the size of the uncut PCR product (198 bp) and that of the larger fragment produced by AatII cleavage of the mutation-containing PCR product (173 bp).…”

Section: Discussionmentioning

confidence: 99%

Complementation of mutant and wild-type human mitochondrial DNAs coexisting since the mutation event and lack of complementation of DNAs introduced separately into a cell within distinct organelles.

1994

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The rules that govern complementation of mutant and wild-type mitochondrial genomes in human cells were investigated under different experimental conditions. Among mitochondrial transformants derived from an individual affected by the MERRF (myoclonus epilepsy associated with ragged red fibers) encephalomyopathy and carrying in heteroplasmic form the mitochondrial tRNALYS mutation associated with that syndrome, normal protein synthesis and respiration was observed when the wild-type mitochondrial DNA exceeded 10% of the total complement. In these transformants, the protective effect of wild-type mitochondrial DNA was shown to involve interactions of the mutant and wild-type gene products. Very different results were obtained in experiments in which two mitochondrial DNAs carrying nonallelic disease-causing mutations were sequentially introduced within distinct organelles into the same human mitochondrial DNA-less (p°) cell. In transformants exhibiting different ratios of the two genomes, no evidence of cooperation between their products was observed, even 3 months after the introduction of the second mutation. These results pointed to the phenotypic independence of the two genomes. A similar conclusion was reached in experiments in which mitochondria carrying a chloramphenicol resistance-inducing mitochondrial DNA mutation were introduced into chloramphenicol-sensitive cells. A plausible interpretation of the different results obtained in the latter two sets of experiments, compared with the complementation behavior observed in the heteroplasmic MERRF transformants, is that in the latter, the mutant and wild-type genomes coexisted in the same organelles from the time of the mutation. This would imply that the way in which mitochondrial DNA is sorted among different organelles plays a fundamental role in determining the oxidative-phosphorylation phenotype in mammalian cells. These results have significant implications for mitochondrial genetics and for studies on the transmission and therapy of mitochondrial DNA-linked diseases.Despite the large number of studies on the expression of artificially produced mitochondrial DNA (mtDNA) mutations and the phenotype of somatic cell hybrids and cybrids, information on mitochondrial genome interactions in mammalian cells is still very limited. The dependence of such interactions on the distribution of the mtDNA molecules among the mitochondria, which changes continuously throughout division and, possibly, fusion of the organelles, and the difficulty of investigating mtDNA sorting in a cell account in part for the present lack of understanding of how much the mitochondrial genomes interact in mammalian cells. The recent discovery of a variety of mtDNA mutations associated with diseases in humans (47) and the growing evidence of accumulation of mtDNA mutations with aging in somatic tissues (12-14, 19, 43) have raised a number of questions about the occurrence and frequency of intermixing of mutant and wild-type mtDNA and/or their products within a cell and the role that co...

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“…Hattori et al, 1991;Cortopassi et al, 1992;Melov et al, 1995). However, over the course of the last decade the non-coding region of mtDNA has been preferred for studies on heteroplasmy distribution (e.g.…”

Section: Discussionmentioning

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

Cited by 567 publications

References 34 publications

Unsolved issues related to human mitochondrial diseases

Unsolved issues related to human mitochondrial diseases

Complementation of mutant and wild-type human mitochondrial DNAs coexisting since the mutation event and lack of complementation of DNAs introduced separately into a cell within distinct organelles.

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

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