Aging-Dependent Large Accumulation of Point Mutations in the Human mtDNA Control Region for Replication

Michikawa, Yuichi; Mazzucchelli, Franca; Bresolin, Nereo; Scarlato, G.; Attardi, Giuseppe

doi:10.1126/science.286.5440.774

Cited by 666 publications

(413 citation statements)

References 30 publications

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“…12 On the other hand, examination of mtDNA revealed high numbers of copy point mutations at specific positions in the control region for replication of human fibroblast mtDNA from normal old, but not young, individuals. 13 In cancers, several studies have reported mtDNA alterations. Tamura et al 14 screened for somatic mutations in the mtDNA control region of gastric adenoma and adenocarcinoma and found that 2 of 45 tumors (4%) had mutations in this region.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial DNA alteration in esophageal cancer

et al. 2001

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It has been reported that various cancers frequently have mutations in the D-loop region of mitochondrial DNA (mtDNA). We examined the genetic alterations in this region of esophageal cancer using direct sequencing. Of 68 sequence variants, 15 have not been reported to date. Tumor mtDNA with these variants were compared with mtDNA from corresponding normal esophageal mucosa. Two of 37 primary esophageal cancers (5%) contained somatic mutations in the D-loop region of mtDNA. Although the mutation rate of mitochondrial tumor DNA within the D-loop was not high, this result suggested that mtDNA mutations play a role in the development of esophageal cancer. © 2001 Wiley-Liss, Inc. Key words: mitochondria; mutation; esophageal cancerEsophageal cancer is one of the most aggressive cancers in the world. Accumulating evidence indicates that a series of genetic changes in dominant oncogenes such as cyclin D1 and hst1/int2 and tumor suppressor genes such as p53 and p16 are involved in the pathogenesis of human esophageal cancer. [1][2][3][4] Recently, it has been proved that genetic changes in mitochondrial DNA (mtDNA) cause a wide variety of diseases. 5 The mitochondrial genome is particularly susceptible to mutations because of the high level of reactive oxygen species (ROS) generation in this organelle, coupled with a low level of DNA repair. 6,7 Polyak et al. 8 found somatic mutations of mtDNA in 7 of 10 (70%) human colorectal cancer cell lines. Subsequently, somatic mitochondrial mutations were identified in various human cancers, and most mutations were found in the D-loop region of mtDNA. 9 Although the D-loop is the noncoding region of the mitochondrial genome, it contains essential transcription and replication elements. Therefore, mutations in the D-loop regulatory region might alter the rate of DNA replication by modifying the binding affinity of important trans-acting factors. This may be why various cancers frequently have mutations in the D-loop region. However, mtDNA alterations have not been reported in esophageal cancer until now.In the present study, we examined the genetic alterations in the D-loop region of mtDNA in esophageal cancer using direct sequencing. We found that 2/37 (5%) esophageal cancers had somatic mutations. Although the mutation rate of mitochondrial tumor DNA within the D-loop was not high, this result suggested that mtDNA mutations play a role in the development of esophageal cancer. MATERIAL AND METHODS Sample collection and DNA preparationThirty-seven primary tumors and corresponding normal tissues were collected at the Nagoya University School of Medicine from esophageal cancer patients who had been diagnosed histologically. All esophageal cancers were squamous cell carcinomas. These samples were obtained during surgery. All tissues were quickly frozen in liquid nitrogen and stored at Ϫ80°C until analysis. We stained frozen sections from the tumors by hematoxylin and eosin (H&E) staining and confirmed that more than 70% of the cells from resected tumor tissues were derived from tumo...

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Section: Discussionmentioning

confidence: 99%

“…Some other reports also indicated that the D-loop region (1.1 kb) might be a hot spot for mutations in mtDNA. 13,17 These results prompted us to examine the D-loop region of mtDNA in esophageal cancers. Using detailed sequence analysis, we found that 2 of 37 esophageal cancers (5%) had genetic alterations in this region.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA alteration in esophageal cancer

et al. 2001

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“…As the damage accumulates, mitochondria lose function. In a 65 year old human about half of the mitochondrial DNA molecules are damaged [7], with a similar loss in mitochondrial respiratory capacity [8].…”

Section: Aging and Diseasementioning

confidence: 99%

Metabolic integration during the evolutionary origin of mitochondria

Searcy

2003

Cell Res

115

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Although mitochondria provide eukaryotic cells with certain metabolic advantages, in other ways they may be disadvantageous. For example, mitochondria produce reactive oxygen species that damage both nucleocytoplasm and mitochondria, resulting in mutations, diseases, and aging. The relationship of mitochondria to the cytoplasm is best understood in the context of evolutionary history. Although it is clear that mitochondria evolved from symbiotic bacteria, the exact nature of the initial symbiosis is a matter of continuing debate. The exchange of nutrients between host and symbiont may have differed from that between the cytoplasm and mitochondria in modern cells. Speculations about the initial relationships include the following.(1) The pre-mitochondrion may have been an invasive, parasitic bacterium. The host did not benefit. (2) The relationship was a nutritional syntrophy based upon transfer of organic acids from host to symbiont. (3) The relationship was a syntrophy based upon H2 transfer from symbiont to host, where the host was a methanogen. (4) There was a syntrophy based upon reciprocal exchange of sulfur compounds. The last conjecture receives support from our detection in eukaryotic cells of substantial H2S-oxidizing activity in mitochondria, and sulfur-reducing activity in the cytoplasm.

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“…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).…”

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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.

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252

149

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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...

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Aging-Dependent Large Accumulation of Point Mutations in the Human mtDNA Control Region for Replication

Cited by 666 publications

References 30 publications

Mitochondrial DNA alteration in esophageal cancer

Mitochondrial DNA alteration in esophageal cancer

Metabolic integration during the evolutionary origin of mitochondria

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

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