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Letters to the Editor |
1 Department of Internal Medicine, College of Medicine, Seonam University, Namwon, South Korea
Departments of2
Laboratory Medicine, and 4
Gastroenterology, Chonnam National University, Medical School and, Chonnam National University, Hwasun Hospital, Hwasun, South Korea
3 Brain Korea 21 Project, Center for Biomedical Human Resources, Chonnam National University, Gwangju, South Korea
aAddress correspondence to this author at: Department of Laboratory Medicine, Chonnam National University Medical School and Chonnam National University Hwasun, Hospital, 160 Ilsimri, Hwasun-eup, Hwasun-gun, Jeollanam-do 519-809, South Korea. Fax 82-61-379-7984; e-mail mgshin{at}chonnam.ac.kr.
To the Editor:
Mitochondrial DNA (mtDNA) is particularly susceptible to oxidative damage and mutations because of the high level of reactive oxygen species (ROS) generated and the inefficiency of the mtDNA repair system. Although the limited repair capacity hypothesis has been validated experimentally in some experimental systems, recent data have shown the existence of base excision repair mechanisms in mammalian mtDNA (1). ROS are commonly released in gastric mucosa inflamed as a result of Helicobacter pylori infection. It is postulated that mtDNA mutations arise in inflamed or chronically damaged gastroduodenal epithelial cells. Therefore, we investigated mtDNA alterations in 25 matched peptic ulcer tissue specimens associated with H. pylori infection, blood samples, and 5 nonulcer tissue samples. The study received institutional review board approval, and all participants gave informed consent.
We used a published protocol to sequence the mtDNA control region and cytochrome b (Cytb) gene and to determine the mtDNA copy number and the qualitative and quantitative profiles of the polyC mtDNA length heteroplasmies in the hypervariable region (HV; 303CCCCCCC309, 303 polyC in HV2 and 16184CCCCCTCCCC16193, 16184 polyC in HV1) (2). We confirmed length heteroplasmy by use of cloning and sequencing and quantified hydrogen peroxide in the peptic ulcer tissue and blood cells with a Bioxytech® H2O2-560TM reagent set (OXIS International). The peptic ulcer tissue was fixed in 4% paraformaldehyde and 1% osmic acid fixatives for electron microscopy.
Many mtDNA sequence variants were identified in the peptic ulcer tissues and corresponding blood cells. Five patients (20%) had ulcer tissue–specific mtDNA substitutions in the hypervariable segment of the control region and the Cytb gene that were not found in the corresponding blood cells (Table 1
). The 303 polyC region is considered a hot spot for somatic mutations in a variety of cancers (3). Another notable example of a homopolymeric polyC tract can be seen in the nucleotide 16184–16193 polyC region in which the T at nucleotide 16189 becomes a C, thereby generating a stretch of 10 or more Cs. Previous studies have suggested that this polymorphism confers a predisposition to diabetes mellitus, lower birth weight, and dilated cardiomyopathy(4). Numerous length heteroplasmic mutations (8 patients, 32%) in the 303 polyC, 16184 polyC, and 514 (CA) repeat regions were also found (Table 1
). For clear and logical understanding of ulcer tissue–specific mtDNA alterations, we performed mtDNA and hydrogen peroxide analysis in 5 matched peripheral blood samples, nonulcer tissues, and ulcer tissues (patients no. 1, 2, 3, 9, and 10). The data of mtDNA variation in nonulcer tissues disclosed the same results from the matched blood samples.
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The oxidative stress elicited by chronic inflammation increases the number of mtDNA mutations and might correlate with a precancerous status (5). The mean (SD) hydrogen peroxide concentration was significantly higher in the supernatants obtained from peptic ulcer tissues [3.8 (0.8) mmol/L] compared with those from the corresponding blood cells [1.3 (0.7) mmol/L; P = 0.012] and nonulcer tissues [1.7 (0.8) mmol/L; P = 0.021]. This high level of ROS might damage the mitochondria, leading to the ultrastructural changes observed on electron microscopy, and the mtDNA mutations. The electron microscopy study of peptic ulcer tissue showed swollen mitochondria and a loss of cristae within the mitochondrial cytoplasm. The mtDNA copy number of the peptic ulcer tissue samples was 
2.5 times higher than that from the blood cells (2 180 547 vs 863 846 copies/µL).
Proposed interactions among host, environment, and H. pylori infection are different in the development of gastric and duodenal ulcers. However, ROS are commonly released in the inflamed gastroduodenal mucosa caused by H. pylori infection after ulcer development. In our limited number of patients we did not observe any significant differences between gastric and duodenal ulcers for ROS level in the supernatants or the frequency and pattern of mtDNA alterations.
In conclusion, mtDNA mutations in peptic ulcer tissues associated with H. pylori infection occur in both the mtDNA control and coding regions. Approximately half of the patients had heteroplasmic mtDNA mutations. The high level of ROS generated by an H. pylori infection might cause mtDNA damage, which can lead to mtDNA mutations in peptic ulcer tissues. The changes in mtDNA in peptic ulcer tissues might further impair ATP synthesis and increase the mtDNA copy number to compensate for the deficiency in ATP. During this perturbation, mitochondria might produce a large amount of ROS, which causes the vicious cycle observed in peptic ulcer disease.
Acknowledgments
Grant/funding support: This study was supported by Grant 0520190-1 from the National R&D Program for Cancer Control, the Ministry of Health and Welfare, Republic of Korea (to M.-G.S.).
Financial disclosures: None declared.
References
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