Accumulation of Somatic Mutation in Mitochondrial DNA and Atherosclerosis in Diabetic Patients

  • Takashi Nomiyama
  • Yasushi Tanaka
  • Lianshan Piao
  • Nobutaka Hattori
  • Hiroshi Uchino
  • Hirotaka Watada
  • Ryuzo Kawamori
  • Shigeo Ohta
Part of the Annals of the New York Academy of Sciences book series (ANYAS, volume 1011)

Abstract

A point mutation of mitochondrial DNA at nucleotide position 3243 A to G is responsible for the genetic cause of diabetes. Otherwise, this mu-tation is also reported to occur as a somatic mutation, possibility because of oxidative stress. Because diabetes may cause oxidative stress, we hypothesized that accumulation of the somatic A3243G mutation in mitochondrial DNA may be accelerated by diabetes. DNA was extracted from blood samples of 290 non-diabetic healthy subjects (aged 0–60 years) and from 383 type 2 diabetic patients (aged 18–80 years). Then, the extent of somatic A3243G mutation in total mitochondrial DNA was detected by real-time polymerase chain reaction (PCR) using the ThqMan probe. The genotyping of ACE I/D or p22phox C242T was done by PCR or PCR-restriction fragment length polymorphism. Although the level of the A3243G mutation was negligible in the newborn group, it increased in healthy subjects aged 20–29 and 41–60 years. In diabetic patients, the mutational rate increased along with age and the duration of diabetes. In the middle-aged group (41–60 years old), the A3243G mutation accumulates fourfold higher in the diabetic patients than in the healthy subjects. Moreover, multiple regression analysis revealed that the most critical factor associated with this mutation in diabetic patients was the duration of diabetes. Furthermore, the genotype of DD, DI-CC (ACE-p22phox) has the highest mutational rate and the thickest intima-media thickness of the carotid artery. In conclusion, diabetes accelerates the accumulation of the somatic A3243G mutation in mitochondrial DNA, and this somatic mutation may be a marker for the duration of diabetes and atherosclerosis.

Keywords

diabetes atherosclerosis mitochondrial DNA somatic mutation oxidative stress 

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References

  1. 1.
    Van den Ouweland, J.M.W. 1992. Mutations in mitochondrial tRNALeu(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat. Genet. 1: 368–371.PubMedCrossRefGoogle Scholar
  2. 2.
    Kadowaki, T. 1994. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N. Engl. J. Med. 330: 962–968.PubMedCrossRefGoogle Scholar
  3. 3.
    Kobayashi, Y. 1990. A point mutation in the mitochondrial tRNA(Leu)(UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). Biochem. Biophys. Res. Commun. 173: 816–822.PubMedCrossRefGoogle Scholar
  4. 4.
    Munscher, C. 1993. Human aging is associated with various point mutations in tRNA gene of mitochondrial DNA. Biol. Chem. Hoppe-Seyler 374: 1099–1104.PubMedCrossRefGoogle Scholar
  5. 5.
    Corral-Debrinski, M. 1992. Mitochondrial DNA deletion in human brain: regional variability and increase with advanced age. Nat. Genet. 2: 324–329.PubMedCrossRefGoogle Scholar
  6. 6.
    Ozawa, T. 1995. Mechanism of somatic mitochondrial DNA mutations associated with age and diseases. Biochem. Biophys. Acta 1271: 177–189.PubMedCrossRefGoogle Scholar
  7. 7.
    Kadenbach, B. 1995. Human aging is associated with stochastic somatic mutations of mitochondrial DNA. Mutat. Res. 338: 161–172.PubMedCrossRefGoogle Scholar
  8. 8.
    Dandona, P. 1993. Oxidative damage to DNA in diabetes mellitus. Lancet 347: 444–445.CrossRefGoogle Scholar
  9. 9.
    Hinokio, Y. 1999. Oxidative damage in diabetes mellitus: its association with diabetic complications. Diabetologia 42: 995–998.PubMedCrossRefGoogle Scholar
  10. 10.
    Kawamori, R. 1995. Asymptomatic hyperglycemia and early atherosclerotic changes. Diabetes Res. Clin. Pract. 40 (Suppl.): S35–S42.CrossRefGoogle Scholar
  11. 11.
    Nishikawa, T. 2000. Normalizing mitochondrial Superoxide production blocks three pathways of hyperglycemic damage. Nature 404: 787–790.PubMedCrossRefGoogle Scholar
  12. 12.
    Cambien, F. 1992. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 359: 641–644.PubMedCrossRefGoogle Scholar
  13. 13.
    Viedt, C. 2000. Differential activation of mitogen-activated protein kinases in smooth muscle cells by angiotensin II: involvement of P22phox and reactive oxygen species. Arterioscler. Thromb. Vasc. Biol. 20: 948–949.Google Scholar
  14. 14.
    Hayashi, J. 1994. Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction. Functional integrity of mitochondrial DNA from aged subjects. J. Biol. Chem. 269: 6878–6883.PubMedGoogle Scholar
  15. 15.
    Inoue, N. 1998. Polymorphism of the NADH/NADPH oxidase p22phox gene in patients with coronary artery disease. Circulation 97: 135–137.PubMedCrossRefGoogle Scholar
  16. 16.
    Kogawa, K. 1997. Effect of polymorphism of apoplipoprotein E and angiotensis-converting enzyme genes on arterial wall thickness. Diabetes 46: 682–687.PubMedCrossRefGoogle Scholar
  17. 17.
    Liang, P. 1997. Increased prevalence of mitochondrial DNA deletions in skeletal muscle of older individuals with impaired glucose tolerance: possible marker of glycemie stress. Diabetes 46: 920–923.PubMedCrossRefGoogle Scholar
  18. 18.
    Fukagawa, N.K. 1999. Aging and high concentrations of glucose potentiate injury to mitochondrial DNA. Free Radie. Biol. Med. 27: 1437–1443.CrossRefGoogle Scholar
  19. 19.
    Suzuki, S. 1999. Oxidative damage to mitochondrial DNA and its relationship to diabetic complications. Diabetes Res. Clin. Pract. 45: 161–168.PubMedCrossRefGoogle Scholar
  20. 20.
    Nomyama, T. 2002. Accumulation of somatic mutation in mitochondrial DNA extracted from peripheral blood cells in diabetic patients. Diabetologia 45: 1577–1583.CrossRefGoogle Scholar
  21. 21.
    Piao, L.S. 2002. Combined genotypes of ACE and NADPH oxidase p22phox associated with somatic mutation of mtDNA and carotid intima-media thickness in Japanese patients with type 2 diabetes mellitus. Curr. Ther. Res. 12: 842–852.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2004

Authors and Affiliations

  • Takashi Nomiyama
    • 1
  • Yasushi Tanaka
    • 1
  • Lianshan Piao
    • 3
  • Nobutaka Hattori
    • 4
  • Hiroshi Uchino
    • 2
  • Hirotaka Watada
    • 2
  • Ryuzo Kawamori
    • 2
  • Shigeo Ohta
    • 4
  1. 1.Department of Medicine, Metabolism and EndocrinologyJuntendo University School of MedicineBunkyo-ku, TokyoJapan
  2. 2.Department of EndocrinologyThe Affiliated Hospital of Yanbian University College of MedicineYanji, JilinChina
  3. 3.Department of NeurologyJuntendo University School of MedicineTokyoJapan
  4. 4.Department of Biochemistry and Cell Biology, Institute of GerontologyNippon Medical SchoolKawasakiJapan

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