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Mitochondrial DNA mutations in the hematopoietic system

Leukemia volume 18, pages 18–22 (2004)Cite this article

In a previous issue of Leukemia, He et al1 report that approximately 40% of patients with acute and chronic leukemias have an acquired (somatic) point mutation of mitochondrial DNA (mtDNA) in their leukemic cells. Are these mutations important for leukemogenesis?

Evidence is accumulating that, as we grow older, the mitochondrial genome becomes mutated in the majority of our cells.2,3,4,5,6,7,8 This is not necessarily related to occupational hazards or other environmental factors. Rather, it appears to be a natural consequence of mitochondrial energy production. mtDNA is in close proximity to the mitochondrial respiratory chain, the main source of reactive oxygen species (ROS). These molecules damage mtDNA, which is not protected by histones.9,10 In addition, DNA repair capacity in the mitochondria is less efficient than in the nucleus. Together, this results in a mutation rate 10- to 20-fold higher than in nuclear DNA.11,12,13,14 Since all 13 protein genes on the small (16 569 kb) mitochondrial genome encode subunits of the mitochondrial respiratory chain, pathogenic mutations in these protein genes lead to impaired ATP production. Mutations in mitochondrial tRNAs and ribosomal RNAs, which are also part of the mitochondrial genome, can have similar effects by interfering with the expression of the mitochondrial-encoded protein genes.

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References

  1. He L, Luo L, Proctor SJ, Middleton PG, Blakely EL, Taylor RW et al. Somatic mitochondrial DNA mutations in adult-onset leukaemia. Leukemia 2003; 17:2487–2491.

    Article  CAS  Google Scholar 

  2. Wallace DC . Mitochondrial diseases in man and mouse. Science 1999; 283: 1482–1488.

    Article  CAS  Google Scholar 

  3. Cortopassi GA, Shibata DD, Soong N-W, Arnheim N . A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 1992; 89: 7370–7374.

    Article  CAS  Google Scholar 

  4. Corral-Debrinski M, Shoffner JM, Lott MT, Wallace DC . Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res 1992; 275: 169–180.

    Article  CAS  Google Scholar 

  5. Kadenbach B, Munscher C, Frank V, Muller-Hocker J, Napiwotzki J . Human ageing is associated with stochastic somatic mutations of mitochondrial DNA. Mutat Res 1995; 338: 161–172.

    Article  CAS  Google Scholar 

  6. Brierley EJ, Johnson MA, Lightowlers RN, James OFW, Turnbull DM . Role of mitochondrial DNA mutations in human aging: implications for the central nervous system and muscle. Ann Neurol 1998; 43: 217–223.

    Article  CAS  Google Scholar 

  7. Murdock DG, Christiacos NC, Wallace DC . The age-related accumulation of a mitochondrial DNA control region mutation in muscle, but not brain, detected by a sensitive PNA-directed PCR clamping based method. Nucleic Acids Res 2000; 28: 4350–4355.

    Article  CAS  Google Scholar 

  8. Coller HA, Bodyak ND, Khrapko K . Frequent intracellular clonal expansions of somatic mtDNA mutations. Ann NY Acad Sci 2002; 959: 434–447.

    Article  CAS  Google Scholar 

  9. Richter C . Reactive oxygen and DNA damage in mitochondria. Mutat Res 1992; 275: 249–255.

    Article  CAS  Google Scholar 

  10. Yakes FM, van Houten B . Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA 1997; 94: 514–519.

    Article  CAS  Google Scholar 

  11. Richter C, Park JW, Ames BN . Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA 1988; 85: 645–646.

    Article  Google Scholar 

  12. Marcelino LA, Thilly WG . Mitochondrial mutagenesis in human cells and tissues. Mutat Res 1999; 434: 177–203.

    Article  CAS  Google Scholar 

  13. Khrapko K, Coller HA, Andre PC, Li X-C, Hanekamp JS, Thilly WG . Mitochondrial mutational spectra in human cells and tissues. Proc Natl Acad Sci USA 1997; 94: 13798–13803.

    Article  CAS  Google Scholar 

  14. Wang E, Wong A, Cortopassi G . The rate of mitochondrial mutagenesis is faster in mice than in humans. Mutat Res 1997; 377: 157–166.

    Article  CAS  Google Scholar 

  15. Ivanova R, Lepage V, Loste MN, Schachter F, Wijnen E, Busson M et al. Mitochondrial DNA sequence variation in human leukemic cells. Int J Cancer 1998; 76: 495–498.

    Article  CAS  Google Scholar 

  16. Shin MG, Kajigaya S, Levin BC, Young NS . Mitochondrial DNA mutations in patients with myelodysplastic syndromes. Blood 2003; 101: 3118–3125.

    Article  CAS  Google Scholar 

  17. Bogenhagen D, Clayton DA . Mouse L cell mitochondrial DNA molecules are selected randomly for replication throughout the cell cycle. Cell 1977; 11: 719–727.

    Article  CAS  Google Scholar 

  18. Elson JL, Samuels DC, Turnbull DM, Chinnery PF . Random intracellular drift explains the clonal expansion of mitochondrial mutations with age. Am J Hum Genet 2001; 68: 802–806.

    Article  CAS  Google Scholar 

  19. Coller HA, Khrapko K, Bodyak ND, Nekhaeva E, Herrero-Jimenez P, Thilly WG . High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nat Genet 2001; 28: 147–150.

    Article  CAS  Google Scholar 

  20. Nekhaeva E, Bodyak ND, Kraytsberg Y, McGrath SB, Van Orsouw NJ, Pluzhnikov A et al. Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues. Proc Natl Acad Sci USA 2002; 99: 5521–5526.

    Article  CAS  Google Scholar 

  21. Chinnery PF, Samuels DC, Elson JL, Turnbull DM . Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 2002; 360: 1323–1325.

    Article  CAS  Google Scholar 

  22. Kraytsberg Y, Nekhaeva E, Bodyak ND, Khrapko K . Mutation and intracellular clonal expansion of mitochondrial genomes: two synergistic components of the aging process? Mech Ageing Dev 2003; 124: 49–53.

    Article  CAS  Google Scholar 

  23. Wallace DC . Mitochondrial DNA mutations and neuromuscular disease. Trends Genet 1989; 5: 9–13.

    Article  CAS  Google Scholar 

  24. Shoubridge EA, Karpati G, Hastings KEM . Deletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease. Cell 1990; 62: 43–49.

    Article  CAS  Google Scholar 

  25. de Grey AD . A proposed refinement of the mitochondrial free radical theory of ageing. BioEssays 1997; 19: 161–166.

    Article  CAS  Google Scholar 

  26. Chinnery PF, Samuels DC . Relaxed replication of mtDNA: a model with implications for the expression of disease. Am J Hum Genet 1999; 64: 1158–1165.

    Article  CAS  Google Scholar 

  27. Hofhaus G, Gattermann N . Mitochondria harbouring mutant mtDNA – a cuckoo in the nest? Biol Chem 1999; 380: 871–877.

    Article  CAS  Google Scholar 

  28. Haraguchi Y, Chung AB, Neill S, Wallace DC . OXBOX and REBOX, overlapping promotor elements of the mitochondrial F0F1–ATP synthase β subunit gene. J Biol Chem 1994; 269: 9330–9334.

    CAS  PubMed  Google Scholar 

  29. Coskun PE, Ruiz-Pesini E, Wallace DC . Control region mtDNA variants: longevity, climatic adaptation, and a forensic conundrum. Proc Natl Acad Sci USA 2003; 100: 2174–2176.

    Article  CAS  Google Scholar 

  30. Gattermann N, Berneburg M, Heinisch J, Aul C, Schneider W . Detection of the ageing-associated 5-kb deletion of mitochondrial DNA in blood and bone marrow of hematologically normal adults. Absence of the deletion in clonal bone marrow disorders. Leukemia 1995; 9: 1704–1710.

    CAS  PubMed  Google Scholar 

  31. Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL . The aging of hematopoietic stem cells. Nat Med 1996; 2: 1011–1016.

    Article  CAS  Google Scholar 

  32. Marley SB, Lewis JL, Davidson RJ, Roberts IAG, Dokal I, Goldman JM et al. Evidence for a continuous decline in haematopoietic cell function from birth: application to evaluating bone marrow failure in children. Br J Haematol 1999; 106: 162–166.

    Article  CAS  Google Scholar 

  33. Geiger H, van Zant G . The aging of lympho-hematopoietic stem cells. Nat Immunol 2002; 3: 329–333.

    Article  CAS  Google Scholar 

  34. Petty RKH, Harding AE, Morgan-Hughes JA . The clinical features of mitochondrial myopathy. Brain 1986; 109: 915–938.

    Article  Google Scholar 

  35. Pearson HA, Lobel JS, Kocoshis SA, Naiman JL, Windmiller J, Lammi AT et al. A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. J Pediatr 1979; 95: 976–984.

    Article  CAS  Google Scholar 

  36. Rötig A, Cormier V, Blanche S, Bonnefont J-P, Ledeist F, Romero N et al. Pearson's marrow–pancreas syndrome. A multisystem mitochondrial disorder in infancy. J Clin Invest 1990; 86: 1601–1608.

    Article  Google Scholar 

  37. Rötig A, Cormier V, Koll F, Mize CE, Saudubray J-M, Veerman A et al. Site-specific deletions of the mitochondrial genome in the Pearson marrow–pancreas syndrome. Genomics 1991; 10: 502–504.

    Article  Google Scholar 

  38. McShane MA, Hammans SR, Sweeney M, Holt IJ, Beattie TJ, Brett EM et al. Pearson syndrome and mitochondrial encephalomyopathy in a patient with a deletion of mtDNA. Am J Hum Genet 1991; 48: 39–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Larsson NG, Holme E, Kristiansson B, Oldfors A, Tulinius M . Progressive increase of the mutated mitochondrial DNA fraction in Kearns–Sayre syndrome. Pediatr Res 1991; 28: 131–133.

    Article  Google Scholar 

  40. Nelson I, Bonne G, Degoul F, Marsac C, Ponsot G, Lestienne P . Kearns–Sayre syndrome with sideroblastic anemia: molecular investigations. Neuropediatrics 1992; 23: 199–205.

    Article  CAS  Google Scholar 

  41. Holt IJ, Harding AE, Cooper JM, Schapira AHV, Toscano A, Clark JB et al. Mitochondrial myopathies: clinical and biochemical features in 30 cases with major deletions of muscle mitochondrial DNA. Ann Neurol 1989; 26: 699–708.

    Article  CAS  Google Scholar 

  42. Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome. N Engl J Med 1989; 320: 1293–1299.

    Article  CAS  Google Scholar 

  43. Ciafaloni E, Ricci E, Shanske S, Moraes CT, Silvestri G, Hirano M et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol 1992; 31: 391–398.

    Article  CAS  Google Scholar 

  44. Goto Y-I, Horai S, Matsuoka T, Koga Y, Nihei K, Kobayashi M et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology 1991; 42: 545–550.

    Article  Google Scholar 

  45. Poulton J, Morten K . Noninvasive diagnosis of the MELAS syndrome from blood DNA. Ann Neurol 1993; 34: 116.

    Article  CAS  Google Scholar 

  46. Rahman S, Poulton J, Marchington D, Suomalainen A . Decrease of 3243 A->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am J Hum Genet 2001; 68: 238–240.

    Article  CAS  Google Scholar 

  47. Holme E, Tulinius MH, Larsson N-G, Oldfors A . Inheritance and expression of mitochondrial DNA point mutations. Biochim Biophys Acta 1995; 1271: 249–252.

    Article  Google Scholar 

  48. Penta JS, Johnson FM, Wachsman JT, Copeland WC . Mitochondrial DNA in human malignancy. Mutat Res 2001; 488: 119–133.

    Article  CAS  Google Scholar 

  49. Löffler M, Jöckel J, Schuster G, Becker C . Dihydroorotate-ubiquinone oxidoreductase links mitochondria in the biosynthesis of pyrimidine nucleotides. Mol Cell Biochem 1997; 174: 125–129.

    Article  Google Scholar 

  50. Gattermann N, Dadak M, Hofhaus G, Wulfert M, Berneburg M, Loeffler ML et al. Severe impairment of nucleotide synthesis through inhibition of mitochondrial respiration. Nucleosides Nucleotides Nucl Acids 2004, (in press).

  51. Kunz BA, Kohalmi SE, Kunkel TA, Mathews CK, McIntosh EM, Reidy JA . Deoxyribonucleoside triphosphate levels: a critical factor in the maintenance of genetic stability. Mutat Res 1994; 318: 1–64.

    Article  CAS  Google Scholar 

  52. Gattermann N . From sideroblastic anemia to the role of mitochondrial DNA mutations in myelodysplastic syndromes. Leukemia Res 2000; 24: 141–151.

    Article  CAS  Google Scholar 

  53. Greenberg PL, Young NS, Gattermann N . Myelodysplastic syndromes. Hematology (Am Soc Hematol Educ Prog) 2002, 136–161.

  54. Buttgereit F, Brand MD . A hierarchy of ATP-consuming processes in mammalian cells. Biochem J 1995; 312: 163–167.

    Article  CAS  Google Scholar 

  55. Kroemer G, Reed JC . Mitochondrial control of cell death. Nat Med 2000; 6: 513–519.

    Article  CAS  Google Scholar 

  56. Wolvetang EJ, Johnson KL, Krauer K, Ralph S, Linnane AW . Mitochondrial respiratory chain inhibitors induce apoptosis. FEBS Lett 1994; 339: 40–44.

    Article  CAS  Google Scholar 

  57. Wang J, Silva JP, Gustafsson CM, Rustin P, Larsson N-G . Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Proc Natl Acad Sci USA 2001; 98: 4038–4043.

    Article  CAS  Google Scholar 

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  1. Klinik für Hämatologie, Onkologie und klinische Immunologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

    N Gattermann

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Gattermann, N. Mitochondrial DNA mutations in the hematopoietic system. Leukemia 18, 18–22 (2004). https://doi.org/10.1038/sj.leu.2403209

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