Mitochondrial dysfunction has been implicated in premature aging, age-related diseases, and tumor initiation and progression. Alterations of the mitochondrial genome accumulate both in aging tissue and tumors. This paper describes our contemporary view of mechanisms by which alterations of the mitochondrial genome contributes to the development of age- and tumor-related pathological conditions. The mechanisms described encompass altered production of mitochondrial ROS, altered regulation of the nuclear epigenome, affected initiation of apoptosis, and a limiting effect on the production of ribonucleotides and deoxyribonucleotides. 1. Introduction Mitochondria are semiautonomous organelles present in almost all eukaryotic cells in quantities ranging from a single copy to several thousands per cell. Important mitochondrial functions include ATP production by oxidative phosphorylation, β-oxidation of fatty acids, and metabolism of amino acids and lipids. Furthermore, mitochondria have a prominent role in apoptosis initiation. The circular mitochondrial DNA (mtDNA) is more susceptible to DNA damages in comparison to nuclear DNA (nDNA). Importantly, mtDNA molecules are not protected by histones, they are supported with only rudimentary DNA repair and are localized in close proximity to the electron transport chain (ETC), which continuously generates oxidizing products known as reactive oxygen species (ROS). Thus, the mutation rate of mtDNA has been reported to be up to 15-fold higher than observed for nDNA in response to DNA damaging agents [1]. Mitochondrial dysfunction and especially dysfunctions caused by mutations of the mtDNA have been implicated with a wide range of age-related pathologies, including cancers, neurodegenerative diseases and, in general, processes that regulate cellular and organismal aging. The mitochondrial genome encodes peptides essential for the function of the ETC and production of ATP by oxidative phosphorylation. Electrons are primarily donated to the ETC from the Krebs cycle, but other sources also contribute. The human enzyme dihydroorotate dehydrogenase (DHODHase), an integral part of the de novo synthesis of pyrimidines, is coupled to the ETC [2, 3]. The activity of the enzyme is dependent on its ability to transfer electrons to the ETC. ATP is the primary product of oxidative phosphorylation, but certain molecules of ROS are also generated continuously [4, 5]. At subtoxic concentrations, ROS has been demonstrated to function as second messenger molecules proposed to report oxygen availability for oxidative phosphorylation and
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.
[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.
[3]
B. Bader, W. Knecht, M. Fries, and M. L？ffler, “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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[26]
O. Warburg, “On the origin of cancer cells,” Science, vol. 123, no. 3191, pp. 309–314, 1956.
[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.
[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.
[29]
J. S. Modica-Napolitano and K. K. Singh, “Mitochondrial dysfunction in cancer,” Mitochondrion, vol. 4, no. 5-6, pp. 755–762, 2004.
[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.
[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.
[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.
[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.
[34]
D. C. Wallace, “Mitochondrial diseases in man and mouse,” Science, vol. 283, no. 5407, pp. 1482–1488, 1999.
[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.
[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.
[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.
[38]
G. Lenaz, “Role of mitochondria in oxidative stress and ageing,” Biochimica et Biophysica Acta, vol. 1366, no. 1-2, pp. 53–67, 1998.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[53]
D. Harman, “Aging: a theory based on free radical and radiation chemistry,” Journal of gerontology, vol. 11, no. 3, pp. 298–300, 1956.
[54]
D. Harman, “The biologic clock: the mitochondria?” Journal of the American Geriatrics Society, vol. 20, no. 4, pp. 145–147, 1972.
[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.
[56]
T. Finkel and N. J. Holbrook, “Oxidants, oxidative stress and the biology of ageing,” Nature, vol. 408, no. 6809, pp. 239–247, 2000.
[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.
[58]
T. Finkel, “Radical medicine: treating ageing to cure disease,” Nature Reviews Molecular Cell Biology, vol. 6, no. 12, pp. 971–976, 2005.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[70]
R. J. Davis, “MAPKs: new JNK expands the group,” Trends in Biochemical Sciences, vol. 19, no. 11, pp. 470–473, 1994.
[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.
[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.
[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.
[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.
[75]
C. Bradham and D. R. McClay, “p38 MAPK in development and cancer,” Cell Cycle, vol. 5, no. 8, pp. 824–828, 2006.
[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.
[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.
[78]
K. K. Singh, “Mitochondria damage checkpoint in apoptosis and genome stability,” FEMS Yeast Research, vol. 5, no. 2, pp. 127–132, 2004.
[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.
[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.
[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.
[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.
[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.
[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.
[85]
M. L？ffler, J. J？ckel, 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.
[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.
[87]
P. Reichard, “Interactions between deoxyribonucleotide and DNA synthesis,” Annual Review of Biochemistry, vol. 57, pp. 349–374, 1988.
[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.
[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.
[90]
B. A. Kunz and S. E. Kohalmi, “Modulation of mutagenesis by deoxyribonucleotide levels,” Annual Review of Genetics, vol. 25, pp. 339–359, 1991.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
