Table of Contents Author Guidelines Submit a Manuscript
Journal of Aging Research
Volume 2011, Article ID 407536, 9 pages
http://dx.doi.org/10.4061/2011/407536
Review Article

The Importance of Mitochondrial DNA in Aging and Cancer

1Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
2Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

Received 16 November 2010; Accepted 31 January 2011

Academic Editor: Alberto Sanz

Copyright © 2011 Claus Desler et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. Richter, J. W. Park, and B. N. Ames, “Normal oxidative damage to mitochondrial and nuclear DNA is extensive,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 17, pp. 6465–6467, 1988. View at Google Scholar · View at Scopus
  2. M. E. Jones, “The genes for and regulation of the enzyme activities of two multifunctional proteins required for the de novo pathway for UMP biosynthesis in mammals,” Molecular Biology, Biochemistry, and Biophysics, vol. 32, pp. 165–182, 1980. View at Google Scholar · View at Scopus
  3. B. Bader, W. Knecht, M. Fries, and M. Löffler, “Expression, purification, and characterization of histidine-tagged rat and human flavoenzyme dihydroorotate dehydrogenase,” Protein Expression and Purification, vol. 13, no. 3, pp. 414–422, 1998. View at Publisher · View at Google Scholar · View at Scopus
  4. D. J. O'Donovan and C. J. Fernandes, “Mitochondrial glutathione and oxidative stress: implications for pulmonary oxygen toxicity in premature infants,” Molecular Genetics and Metabolism, vol. 71, no. 1-2, pp. 352–358, 2000. View at Publisher · View at Google Scholar · View at Scopus
  5. S. Melova, J. A. Schneider, P. E. Coskun, D. A. Bennett, and D. C. Wallace, “Mitochondrial DNA rearrangements in aging human brain and in situ PCR of mtDNA,” Neurobiology of Aging, vol. 20, no. 5, pp. 565–571, 1999. View at Publisher · View at Google Scholar · View at Scopus
  6. F. Weinberg and N. S. Chandel, “Mitochondrial metabolism and cancer,” Annals of the New York Academy of Sciences, vol. 1177, pp. 66–73, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. D. Boffoli, S. C. Scacco, R. Vergari, G. Solarino, G. Santacroce, and S. Papa, “Decline with age of the respiratory chain activity in human skeletal muscle,” Biochimica et Biophysica Acta, vol. 1226, no. 1, pp. 73–82, 1994. View at Publisher · View at Google Scholar · View at Scopus
  8. K. R. Short, M. L. Bigelow, J. Kahl et al., “Decline in skeletal muscle mitochondrial function with aging in humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 15, pp. 5618–5623, 2005. View at Publisher · View at Google Scholar · View at Scopus
  9. G. H. Herbener, “A morphometric study of age dependent changes in mitochondrial populations of mouse liver and heart,” Journals of Gerontology, vol. 31, no. 1, pp. 8–12, 1976. View at Google Scholar · View at Scopus
  10. P. D. Wilson and L. M. Franks, “The effect of age on mitochondrial ultrastructure and enzymes,” Advances in Experimental Medicine and Biology, vol. 53, pp. 171–183, 1975. View at Google Scholar · View at Scopus
  11. J. Lipetz and V. J. Cristofalo, “Ultrastructural changes accompanying the aging of human diploid cells in culture,” Journal of Ultrasructure Research, vol. 39, no. 1-2, pp. 43–56, 1972. View at Google Scholar · View at Scopus
  12. K. Hattori, M. Tanaka, S. Sugiyama et al., “Age-dependent increase in deleted mitochondrial DNA in the human heart: possible contributory factor to presbycardia,” American Heart Journal, vol. 121, no. 6 I, pp. 1735–1742, 1991. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Corral-Debrinski, T. Horton, M. T. Lott, J. M. Shoffner, M. F. Beal, and D. C. Wallace, “Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age,” Nature Genetics, vol. 2, no. 4, pp. 324–329, 1992. View at Google Scholar · View at Scopus
  14. G. A. Cortopassi and N. Arnheim, “Detection of a specific mitochondrial DNA deletion in tissues of older humans,” Nucleic Acids Research, vol. 18, no. 23, pp. 6927–6933, 1990. View at Google Scholar · View at Scopus
  15. Y. Michikawa, F. Mazzucchelli, N. Bresolin, G. Scarlato, and G. Attardi, “Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication,” Science, vol. 286, no. 5440, pp. 774–779, 1999. View at Publisher · View at Google Scholar · View at Scopus
  16. R. W. Taylor, M. J. Barron, G. M. Borthwick et al., “Mitochondrial DNA mutations in human colonic crypt stem cells,” Journal of Clinical Investigation, vol. 112, no. 9, pp. 1351–1360, 2003. View at Publisher · View at Google Scholar · View at Scopus
  17. L. A. Gómez, J. S. Monette, J. D. Chavez, C. S. Maier, and T. M. Hagen, “Supercomplexes of the mitochondrial electron transport chain decline in the aging rat heart,” Archives of Biochemistry and Biophysics, vol. 490, no. 1, pp. 30–35, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. G. Barja and A. Herrero, “Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals,” FASEB Journal, vol. 14, no. 2, pp. 312–318, 2000. View at Google Scholar · View at Scopus
  19. D. Zhang, J. L. Mott, S. W. Chang, M. Stevens, P. Mikolajczak, and H. P. Zassenhaus, “Mitochondrial DNA mutations activate programmed cell survival in the mouse heart,” American Journal of Physiology, vol. 288, no. 5, pp. H2476–H2483, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. S. Vielhaber, D. Kunz, K. Winkler et al., “Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis,” Brain, vol. 123, no. 7, pp. 1339–1348, 2000. View at Google Scholar · View at Scopus
  21. Z. Ungvari, W. E. Sonntag, and A. Csiszar, “Mitochondria and aging in the vascular system,” Journal of Molecular Medicine, vol. 88, no. 10, pp. 1021–1027, 2010. View at Publisher · View at Google Scholar
  22. A. Trifunovic, A. Wredenberg, M. Falkenberg et al., “Premature ageing in mice expressing defective mitochondrial DNA polymerase,” Nature, vol. 429, no. 6990, pp. 417–423, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. C. C. Kujoth, A. Hiona, T. D. Pugh et al., “Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging,” Science, vol. 309, no. 5733, pp. 481–484, 2005. View at Publisher · View at Google Scholar · View at Scopus
  24. F. N. Brand, D. K. Kiely, W. B. Kannel, and R. H. Myers, “Family patterns of coronary heart disease mortality: the Framingham Longevity Study,” Journal of Clinical Epidemiology, vol. 45, no. 2, pp. 169–174, 1992. View at Publisher · View at Google Scholar · View at Scopus
  25. M. F. Alexeyev, S. P. LeDoux, and G. L. Wilson, “Mitochondrial DNA and aging,” Clinical Science, vol. 107, no. 4, pp. 355–364, 2004. View at Publisher · View at Google Scholar · View at Scopus
  26. O. Warburg, “On the origin of cancer cells,” Science, vol. 123, no. 3191, pp. 309–314, 1956. View at Google Scholar · View at Scopus
  27. J. S. Penta, F. M. Johnson, J. T. Wachsman, and W. C. Copeland, “Mitochondrial DNA in human malignancy,” Mutation Research, vol. 488, no. 2, pp. 119–133, 2001. View at Publisher · View at Google Scholar · View at Scopus
  28. J. S. Modica-Napolitano and K. K. Singh, “Mitochondria as targets for detection and treatment of cancer,” Expert Reviews in Molecular Medicine, vol. 4, no. 9, pp. 1–19, 2002. View at Google Scholar
  29. J. S. Modica-Napolitano and K. K. Singh, “Mitochondrial dysfunction in cancer,” Mitochondrion, vol. 4, no. 5-6, pp. 755–762, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. K. K. Singh, M. Kulawiec, I. Still, M. M. Desouki, J. Geradts, and S.-I. Matsui, “Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis,” Gene, vol. 354, no. 1-2, pp. 140–146, 2005. View at Publisher · View at Google Scholar
  31. M. Kulawiec, H. Arnouk, M. M. Desouki, L. Kazim, I. Still, and K. K. Singh, “Proteomic analysis of mitochondria-to-nucleus retrograde response in human cancer,” Cancer Biology and Therapy, vol. 5, no. 8, pp. 967–975, 2006. View at Google Scholar · View at Scopus
  32. J. A. Petros, A. K. Baumann, E. Ruiz-Pesini et al., “MtDNA mutations increase tumorigenicity in prostate cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 3, pp. 719–724, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. Y. Shidara, K. Yamagata, T. Kanamori et al., “Positive contribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis,” Cancer Research, vol. 65, no. 5, pp. 1655–1663, 2005. View at Publisher · View at Google Scholar · View at Scopus
  34. D. C. Wallace, “Mitochondrial diseases in man and mouse,” Science, vol. 283, no. 5407, pp. 1482–1488, 1999. View at Publisher · View at Google Scholar · View at Scopus
  35. S. DiMauro and E. A. Schon, “Mitochondrial respiratory-chain diseases,” The New England Journal of Medicine, vol. 348, no. 26, pp. 2656–2668, 2003. View at Publisher · View at Google Scholar · View at Scopus
  36. G. Fayet, M. Jansson, D. Sternberg et al., “Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function,” Neuromuscular Disorders, vol. 12, no. 5, pp. 484–493, 2002. View at Publisher · View at Google Scholar · View at Scopus
  37. T. Ozawa, “Mechanism of somatic mitochondrial DNA mutations associated with age and diseases,” Biochimica et Biophysica Acta, vol. 1271, no. 1, pp. 177–189, 1995. View at Publisher · View at Google Scholar · View at Scopus
  38. G. Lenaz, “Role of mitochondria in oxidative stress and ageing,” Biochimica et Biophysica Acta, vol. 1366, no. 1-2, pp. 53–67, 1998. View at Publisher · View at Google Scholar · View at Scopus
  39. A. W. Linnane, S. Marzuki, T. Ozawa, and M. Tanaka, “Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases,” The Lancet, vol. 1, no. 8639, pp. 642–645, 1989. View at Google Scholar · View at Scopus
  40. A. Bender, K. J. Krishnan, C. M. Morris et al., “High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease,” Nature Genetics, vol. 38, no. 5, pp. 515–517, 2006. View at Publisher · View at Google Scholar · View at Scopus
  41. A. D. N. J. De Grey, “A proposed refinement of the mitochondrial free radical theory of aging,” BioEssays, vol. 19, no. 2, pp. 161–166, 1997. View at Google Scholar
  42. J. L. Elson, D. C. Samuels, D. M. Turnbull, and P. F. Chinnery, “Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age,” American Journal of Human Genetics, vol. 68, no. 3, pp. 802–806, 2001. View at Publisher · View at Google Scholar · View at Scopus
  43. C. Y. Lu, H. C. Lee, H. J. Fahn, and Y. H. Wei, “Oxidative damage elicited by imbalance of free radical scavenging enzymes is associated with large-scale mtDNA deletions in aging human skin,” Mutation Research, vol. 423, no. 1-2, pp. 11–21, 1999. View at Publisher · View at Google Scholar · View at Scopus
  44. T. Ide, H. Tsutsui, S. Kinugawa et al., “Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium,” Circulation Research, vol. 85, no. 4, pp. 357–363, 1999. View at Google Scholar · View at Scopus
  45. Q. Chen, E. J. Vazquez, S. Moghaddas, C. L. Hoppel, and E. J. Lesnefsky, “Production of reactive oxygen species by mitochondria: central role of complex III,” Journal of Biological Chemistry, vol. 278, no. 38, pp. 36027–36031, 2003. View at Publisher · View at Google Scholar · View at Scopus
  46. E. J. Lesnefsky, T. I. Gudz, S. Moghaddas et al., “Aging decreases electron transport complex III activity in heart interfibrillar mitochondria by alteration of the cytochrome c binding site,” Journal of Molecular and Cellular Cardiology, vol. 33, no. 1, pp. 37–47, 2001. View at Publisher · View at Google Scholar · View at Scopus
  47. R. F. Castilho, A. J. Kowaltowski, A. R. Meinicke, and A. E. Vercesi, “Oxidative damage of mitochondria induced by Fe(II)citrate or t-butyl hydroperoxlde in the presence of Ca2+: effect of coenzyme Q redox state,” Free Radical Biology and Medicine, vol. 18, no. 1, pp. 55–59, 1995. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Arai, H. Imai, T. Koumura et al., “Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells,” Journal of Biological Chemistry, vol. 274, no. 8, pp. 4924–4933, 1999. View at Publisher · View at Google Scholar · View at Scopus
  49. T. W. Simmons and I. S. Jamall, “Relative importance of intracellular glutathione peroxidase and catalase in vivo for prevention of peroxidation to the heart,” Cardiovascular Research, vol. 23, no. 9, pp. 774–779, 1989. View at Google Scholar · View at Scopus
  50. R. Radi, J. F. Turrens, L. Y. Chang, K. M. Bush, J. D. Crapo, and B. A. Freeman, “Detection of catalase in rat heart mitochondria,” Journal of Biological Chemistry, vol. 266, no. 32, pp. 22028–22034, 1991. View at Google Scholar · View at Scopus
  51. T. Tabatabaie and R. A. Floyd, “Inactivation of glutathione peroxidase by benzaldehyde,” Toxicology and Applied Pharmacology, vol. 141, no. 2, pp. 389–393, 1996. View at Publisher · View at Google Scholar · View at Scopus
  52. A. C. M. Filho and R. Meneghini, “In vivo formation of single-strand breaks in DNA by hydrogen peroxide is mediated by the Haber-Weiss reaction,” Biochimica et Biophysica Acta, vol. 781, no. 1-2, pp. 56–63, 1984. View at Google Scholar · View at Scopus
  53. D. Harman, “Aging: a theory based on free radical and radiation chemistry,” Journal of gerontology, vol. 11, no. 3, pp. 298–300, 1956. View at Google Scholar · View at Scopus
  54. D. Harman, “The biologic clock: the mitochondria?” Journal of the American Geriatrics Society, vol. 20, no. 4, pp. 145–147, 1972. View at Google Scholar · View at Scopus
  55. D. Harman, “Free radical theory of aging: an update—increasing the functional life span,” Annals of the New York Academy of Sciences, vol. 1067, no. 1, pp. 10–21, 2006. View at Publisher · View at Google Scholar · View at Scopus
  56. T. Finkel and N. J. Holbrook, “Oxidants, oxidative stress and the biology of ageing,” Nature, vol. 408, no. 6809, pp. 239–247, 2000. View at Publisher · View at Google Scholar · View at Scopus
  57. M. L. Genova, M. M. Pich, A. Bernacchia et al., “The mitochondrial production of reactive oxygen species in relation to aging and pathology,” Annals of the New York Academy of Sciences, vol. 1011, pp. 86–100, 2004. View at Publisher · View at Google Scholar · View at Scopus
  58. T. Finkel, “Radical medicine: treating ageing to cure disease,” Nature Reviews Molecular Cell Biology, vol. 6, no. 12, pp. 971–976, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. B. G. Slane, N. Aykin-Burns, B. J. Smith et al., “Mutation of succinate dehydrogenase subunit C results in increased O2, oxidative stress, and genomic instability,” Cancer Research, vol. 66, no. 15, pp. 7615–7620, 2006. View at Publisher · View at Google Scholar · View at Scopus
  60. J. S. Park, L. K. Sharma, H. Li et al., “A heteroplasmic, not homoplasmic, mitochondrial DNA mutation promotes tumorigenesis via alteration in reactive oxygen species generation and apoptosis,” Human Molecular Genetics, vol. 18, no. 9, pp. 1578–1589, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. S. E. Schriner, N. J. Linford, G. M. Martin et al., “Extension of murine life span by overexpression of catalase targeted to mitochondria,” Science, vol. 308, no. 5730, pp. 1909–1911, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. D. Li, Y. Lai, Y. Yue, P. S. Rabinovitch, C. Hakim, and D. Duan, “Ectopic catalase expression in mitochondria by adeno-associated virus enhances exercise performance in mice,” PLoS One, vol. 4, no. 8, Article ID e6673, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. P. M. Treuting, N. J. Linford, S. E. Knoblaugh et al., “Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria,” The Journals of Gerontology Series A, vol. 63, no. 8, pp. 813–824, 2008. View at Google Scholar · View at Scopus
  64. V. Adler, Z. Yin, K. D. Tew, and Z. Ronai, “Role of redox potential and reactive oxygen species in stress signaling,” Oncogene, vol. 18, no. 45, pp. 6104–6111, 1999. View at Google Scholar · View at Scopus
  65. S. M. Welford, B. Bedogni, K. Gradin, L. Poellinger, M. B. Powell, and A. J. Giaccia, “HIF1α delays premature senescence through the activation of MIF,” Genes and Development, vol. 20, no. 24, pp. 3366–3371, 2006. View at Publisher · View at Google Scholar · View at Scopus
  66. P. H. Maxwell, M. S. Wlesener, G. W. Chang et al., “The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis,” Nature, vol. 399, no. 6733, pp. 271–275, 1999. View at Publisher · View at Google Scholar · View at Scopus
  67. N. S. Chandel, E. Maltepe, E. Goldwasser, C. E. Mathieu, M. C. Simon, and P. T. Schumacker, “Mitochondrial reactive oxygen species trigger hypoxia-induced transcription,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 20, pp. 11715–11720, 1998. View at Publisher · View at Google Scholar · View at Scopus
  68. N. S. Chandel, W. C. Trzyna, D. S. McClintock, and P. T. Schumacker, “Role of oxidants in NF-κB activation and TNF-α gene transcription induced by hypoxia and endotoxin,” Journal of Immunology, vol. 165, no. 2, pp. 1013–1021, 2000. View at Google Scholar · View at Scopus
  69. P. Carmeliet, Y. Dor, J.-M. Herber et al., “Role of HIF-1± in hypoxiamediated apoptosis, cell proliferation and tumour angiogenesis,” Nature, vol. 394, no. 6692, pp. 485–490, 1998. View at Publisher · View at Google Scholar
  70. R. J. Davis, “MAPKs: new JNK expands the group,” Trends in Biochemical Sciences, vol. 19, no. 11, pp. 470–473, 1994. View at Publisher · View at Google Scholar · View at Scopus
  71. A. Kulisz, N. Chen, N. S. Chandel, Z. Shao, and P. T. Schumacker, “Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes,” American Journal of Physiology, vol. 282, no. 6, pp. L1324–L1329, 2002. View at Google Scholar · View at Scopus
  72. Y. J. Lee, H. N. Cho, J. W. Soh et al., “Oxidative stress-induced apoptosis is mediated by ERK1/2 phosphorylation,” Experimental Cell Research, vol. 291, no. 1, pp. 251–266, 2003. View at Publisher · View at Google Scholar · View at Scopus
  73. Y. A. Lee and M. H. Shin, “Mitochondrial respiration is required for activation of ERK1/2 and caspase-3 in human eosinophils stimulated with hydrogen peroxide,” Journal of Investigational Allergology and Clinical Immunology, vol. 19, no. 3, pp. 188–194, 2009. View at Google Scholar · View at Scopus
  74. N. Li, K. Ragheb, G. Lawler et al., “Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production,” Journal of Biological Chemistry, vol. 278, no. 10, pp. 8516–8525, 2003. View at Publisher · View at Google Scholar · View at Scopus
  75. C. Bradham and D. R. McClay, “p38 MAPK in development and cancer,” Cell Cycle, vol. 5, no. 8, pp. 824–828, 2006. View at Google Scholar · View at Scopus
  76. M. Kohno and J. Pouyssegur, “Targeting the ERK signaling pathway in cancer therapy,” Annals of Medicine, vol. 38, no. 3, pp. 200–211, 2006. View at Publisher · View at Google Scholar · View at Scopus
  77. A. Rasola, M. Sciacovelli, F. Chiara, B. Pantic, W. S. Brusilow, and P. Bernardi, “Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 2, pp. 726–731, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. K. K. Singh, “Mitochondria damage checkpoint in apoptosis and genome stability,” FEMS Yeast Research, vol. 5, no. 2, pp. 127–132, 2004. View at Publisher · View at Google Scholar · View at Scopus
  79. D. J. Smiraglia, M. Kulawiec, G. L. Bistulfi, S. G. Gupta, and K. K. Singh, “A novel role for mitochondria in regulating epigenetic modification in the nucleus,” Cancer Biology and Therapy, vol. 7, no. 8, pp. 1182–1190, 2008. View at Google Scholar · View at Scopus
  80. A. Hiona, A. Sanz, G. C. Kujoth et al., “Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice,” PLoS One, vol. 5, no. 7, Article ID e11468, 2010. View at Publisher · View at Google Scholar
  81. E. Gottlieb, S. M. Armour, M. H. Harris, and C. B. Thompson, “Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis,” Cell Death and Differentiation, vol. 10, no. 6, pp. 709–717, 2003. View at Publisher · View at Google Scholar · View at Scopus
  82. M. Nooteboom, R. Johnson, R. W. Taylor et al., “Age-associated mitochondrial DNA mutations lead to small but significant changes in cell proliferation and apoptosis in human colonic crypts,” Aging Cell, vol. 9, no. 1, pp. 96–99, 2010. View at Publisher · View at Google Scholar · View at Scopus
  83. C. Desler, A. Lykke, and L. J. Rasmussen, “The effect of mitochondrial dysfunction on cytosolic nucleotide metabolism,” Journal of Nucleic Acids, vol. 2010, Article ID 701518, 9 pages, 2010. View at Publisher · View at Google Scholar
  84. C. Desler, B. Munch-Petersen, T. Stevnsner et al., “Mitochondria as determinant of nucleotide pools and chromosomal stability,” Mutation Research, vol. 625, no. 1-2, pp. 112–124, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. M. Löffler, J. Jöckel, G. Schuster, and C. Becker, “Dihydroorotat-ubiquinone oxidoreductase links mitochondria in the biosynthesis of pyrimidine nucleotides,” Molecular and Cellular Biochemistry, vol. 174, no. 1-2, pp. 125–129, 1997. View at Publisher · View at Google Scholar · View at Scopus
  86. P. Y. Ke, Y. Y. Kuo, C. M. Hu, and Z. F. Chang, “Control of dTTP pool size by anaphase promoting complex/cyclosome is essential for the maintenance of genetic stability,” Genes and Development, vol. 19, no. 16, pp. 1920–1933, 2005. View at Publisher · View at Google Scholar · View at Scopus
  87. P. Reichard, “Interactions between deoxyribonucleotide and DNA synthesis,” Annual Review of Biochemistry, vol. 57, pp. 349–374, 1988. View at Google Scholar · View at Scopus
  88. K. Bebenek and T. A. Kunkel, “Frameshift errors initiated by nucleoside misincorporation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 13, pp. 4946–4950, 1990. View at Publisher · View at Google Scholar · View at Scopus
  89. P. B. Jacky, B. Beek, and G. R. Sutherland, “Fragile sites in chromosomes: possible model for the study of spontaneous chromosome breakage,” Science, vol. 220, no. 4592, pp. 69–70, 1983. View at Google Scholar · View at Scopus
  90. B. A. Kunz and S. E. Kohalmi, “Modulation of mutagenesis by deoxyribonucleotide levels,” Annual Review of Genetics, vol. 25, pp. 339–359, 1991. View at Google Scholar · View at Scopus
  91. R. G. Wickremasinghe and A. V. Hoffbrand, “Reduced rate of DNA replication fork movement in megaloblastic anemia,” Journal of Clinical Investigation, vol. 65, no. 1, pp. 26–36, 1980. View at Google Scholar · View at Scopus
  92. I. Grummt and F. Grummt, “Control of nucleolar RNA synthesis by the intracellular pool sizes of ATP and GTP,” Cell, vol. 7, no. 3, pp. 447–453, 1976. View at Google Scholar · View at Scopus
  93. M. Kondo, T. Yamaoka, S. Honda et al., “The rate of cell growth is regulated by purine biosynthesis via ATP production and G1 to S phase transition,” Journal of Biochemistry, vol. 128, no. 1, pp. 57–64, 2000. View at Google Scholar · View at Scopus
  94. L. Quéméneur, L. M. Gerland, M. Flacher, M. Ffrench, J. P. Revillard, and L. Genestier, “Differential control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and pyrimidine nucleotides,” Journal of Immunology, vol. 170, no. 10, pp. 4986–4995, 2003. View at Google Scholar · View at Scopus
  95. S. P. Linke, K. C. Clarkin, A. Di Leonardo, A. Tsou, and G. M. Wahl, “A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage,” Genes and Development, vol. 10, no. 8, pp. 934–947, 1996. View at Google Scholar · View at Scopus
  96. L. L. Bennett, D. Smithers, L. M. Rose, D. J. Adamson, and H. J. Thomas, “Inhibition of synthesis of pyrimidine nucleotides by 2-hydroxy-3-(3,3-dichloroallyl)-1,4-naphthoquinone,” Cancer Research, vol. 39, no. 12, pp. 4868–4874, 1979. View at Google Scholar · View at Scopus
  97. S. Liu, E. A. Neidhardt, T. H. Grossman, T. Ocain, and J. Clardy, “Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents,” Structure, vol. 8, no. 1, pp. 25–33, 2000. View at Publisher · View at Google Scholar · View at Scopus
  98. A. S. F. Chong, K. Rezai, H. M. Gebel et al., “Effects of leflunomide and other immunosuppressive agents on T cell proliferation in vitro,” Transplantation, vol. 61, no. 1, pp. 140–145, 1996. View at Publisher · View at Google Scholar · View at Scopus
  99. K. Rückemann, L. D. Fairbanks, E. A. Carrey et al., “Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans,” Journal of Biological Chemistry, vol. 273, no. 34, pp. 21682–21691, 1998. View at Publisher · View at Google Scholar · View at Scopus
  100. S. Greene, K. Watanabe, J. Braatz-Trulson, and L. Lou, “Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide,” Biochemical Pharmacology, vol. 50, no. 6, pp. 861–867, 1995. View at Publisher · View at Google Scholar · View at Scopus
  101. H. M. Cherwinski, N. Byars, S. J. Ballaron, G. M. Nakano, J. M. Young, and J. T. Ransom, “Leflunomide interferes with pyrimidine nucleotide biosynthesis,” Inflammation Research, vol. 44, no. 8, pp. 317–322, 1995. View at Publisher · View at Google Scholar · View at Scopus
  102. M. Grégoire, R. Morais, M. A. Quilliam, and D. Gravel, “On auxotrophy for pyrimidines of respiration-deficient chick embryo cells,” European Journal of Biochemistry, vol. 142, no. 1, pp. 49–55, 1984. View at Google Scholar · View at Scopus
  103. M. P. King and G. Attardi, “Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation,” Science, vol. 246, no. 4929, pp. 500–503, 1989. View at Google Scholar · View at Scopus