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研究生:葉家伶
研究生(外文):Chia-Lin Yeh
論文名稱:人類細胞在氧化壓力下DNA聚合酶Gamma與粒線體DNA含量之變化
論文名稱(外文):Alteration of DNA Polymerase Gamma and Mitochondrial DNA Content in Human Cells under Oxidative Stress
指導教授:魏耀揮魏耀揮引用關係
指導教授(外文):Yau-Huei Wei
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:84
中文關鍵詞:粒線體
外文關鍵詞:mitochondria
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罹患MERRF症候群的患者約有85%帶有粒線體DNA tRNALys基因上的A8344G點突變,造成粒線體呼吸鏈功能的缺陷,細胞內累積較多的ROS;而不正常的粒線體增生與聚集所造成的肌肉組織中糙紅肌絲纖維則為MERRF臨床診斷的重要依據。因此,我們認為過多的ROS可能在粒線體增生機轉裡扮演重要的角色。本研究先以不同低劑量的過氧化氫處理人類骨髓癌143B細胞,再利用三株正常人(N1-N3)與三株MERRF症候群患者(M1-M3)的皮膚纖維母細胞,探討在不同氧化壓力下細胞內粒線體DNA增生之機制及其與MERRF症候群致病機轉的關係。結果顯示,以過氧化氫0-500 �嵱之濃度下處理143B細胞48小時後,細胞內的ROS含量隨過氧化氫濃度分別上升了1.6、1.9、2.1、2.1及2.4倍,而粒線體DNA氧化損傷程度則分別上升1.9、3.1、4.8、6.0及6.9倍,兩者皆呈現濃度與時間依賴性的增加。粒線體DNA套數與負責粒線體DNA複製與修復的Pol �袕J白質表現量,則在200 �嵱過氧化氫處理下達到顛峰,分別增加為1.5與2.0倍,之後隨著過氧化氫濃度增加而下降,粒線體DNA套數於500 �嵱過氧化氫處理下顯著低於未處理的控制組約50%,Pol gamma�袕J白質表現量則與控制組無顯著差異。我們推測在較低程度氧化壓力下,ROS可能在細胞中扮演訊息傳遞的功能,提升粒線體DNA複製與轉錄的活性,作為ROS造成粒線體傷害之代償性調控。但是,在較高程度氧化壓力下,則可造成細胞內生化分子的氧化性傷害,增加Pol �袕J白質的降解速率與氧化傷害而降低活性,使得粒線體DNA的含量降低。另外,在三株MERRF症候群患者皮膚纖維母細胞中,我們發現其細胞內源性過氧化氫的含量、粒線體DNA套數與粒線體DNA氧化損傷程度分別比三株正常皮膚纖維母細胞之平均值高出1.8、1.6及2.9倍,但是MERRF患者細胞中Pol gamma�袕J白質表現量卻與細胞內ROS的含量呈反比。我們推測由於MERRF症候群患者細胞內部分粒線體DNA本身就有突變或損傷,當初期ROS誘發代償性調控,使粒線體DNA複製與轉錄速率增加,Pol gammma�蚹Q用含有突變的粒線體DNA作為模版進行複製時,會因此累積品質不良或含有突變的粒線體DNA。但是長期患者的組織細胞處在低氧化壓力之下,Pol gamma�蚸鷎D受氧化傷害使表現量或活性降低,最終造成MERRF症候群患者細胞內ROS上升、粒線體DNA含量與損傷增加以及Pol gamma�袕J白質表現量與細胞內ROS含量呈反比的現象。綜合在143B細胞模式下以及在MERRF症候群患者皮膚纖維母細胞的研究成果,我們認為因外在過氧化氫或細胞本身粒線體DNA突變所造成的氧化壓力之惡性循環可能經由調控Pol gamma�蛈b143B細胞以及MERRF症候群患者細胞粒線體DNA增量機轉中扮演一個重要的角色。
About 85% of the patients with myoclonic epilepsy and ragged-red fibers (MERRF) syndrome have been found to carry the A8344G mutation in the tRNALys gene of mitochondrial DNA (mtDNA). The cells harboring this mtDNA mutation show reduced activities of respiratory chain enzymes and generate more reactive oxygen species (ROS). Histochemical analysis of skeletal muscle biopsies of MERRF patients often reveal the presence of ragged-red fibers, which represent subsarcolemmal accumulation of abnormal mitochondria. We have suggested that excess ROS may play an important role in mitochondrial biogenesis. In this study, experiments have been designed to investigate the mechanisms underlying the changes of mtDNA content under different levels of oxidative stress in 143B cells induced by H2O2. We then conducted similar studies using skin fibroblasts from normal subjects (N1-N3) and patients with MERRF syndrome (M1-M3) to unravel possible role of oxidative stress response in the pathogenesis of MERRF syndrome. The results showed that the intracellular ROS and mtDNA oxidative damages were respectively increased 1.6, 1.9, 2.1, 2.1, 2.4 fold and 1.9, 3.1, 4.8, 6.0, 6.9 fold in the concentration- and time-dependent manner after 0-500 �嵱 H2O2 treatment for 48 hours. Moreover, the mtDNA content and the protein expression of DNA polymerase gamma (Pol ��) were increased, 1.5 and 2.0 fold respectively, by treatment with 200 �嵱 H2O2. However, the mtDNA content was dramatically decreased to about 50% of that of control, while Pol �� was decreased to the basal level after 500 �嵱 H2O2 treatment. These findings suggest that ROS might induce mtDNA replication and transcription to compensate for the oxidative damage caused by ROS under mild oxidative stress. Under higher oxidative stress, ROS may interrupt transcription and translation of the genes required for the maintenance of mtDNA, resulting in the reduction of protein expression or activity of Pol ��, which in return may cause a decrease of the copy number of mtDNA. On the other hand, we found that the endogenous levels of H2O2, mtDNA copy number and mtDNA oxidative damage in MERRF skin fibroblasts were 1.8, 1.6 and 2.9 fold higher than those of normal subjects, but the protein expression level of Pol ���nwas inversely correlated with the intracellular ROS in MERRF skin fibroblasts. Thus, we suggest that the intracellular ROS produced by defective respiratory enzymes of the damaged mtDNA may initiate an increase of mtDNA replication to compensate for the oxidative damage. Consquently, accumulation of mutated mtDNA may be a result of the replication of mutated mtDNA by Pol ���n. The protein expression or enzyme activity of Pol ���nmay be decreased by oxidative damage under low oxidative stress over a long period of time in the affected tissues of patients. These molecular changes cause an increase of intracellular ROS and mtDNA copy number, damage of mtDNA, and a decrease in the expression of Pol ��. Based on these findings, we suggest that an oxidative stress-elicited vicious cycle may play an important role in the pathophysiology of mitochondrial diseases such as MERRF syndrome through the regulation of Pol ���nand mtDNA content in affected tissues of the patients.
中文摘要 ……………………………………… 2
英文摘要 ……………………………………… 4
縮寫表 ……………………………………… 6
緒論 ……………………………………… 8
實驗材料與方法 ……………………………………… 21
實驗結果 ……………………………………… 32
討論 ……………………………………… 39
參考文獻 ……………………………………… 49
表與圖 ……………………………………… 64
1. Gray, M.W. (1993) Origin and evolution of organelle genomes. Curr. Opin. Genet. Dev. 3, 884-890.
2. Gray, M.W., Burger, G. and Lang, B.F. (1999) Mitochondrial evolution. Science 283, 1476-1481.
3. Scheffler, I.E. (2001) Mitochondria make a come back. Adv. Drug Deliv. Rev. 49, 3-26.
4. Hatefi, Y. (1985) The mitochondrial electron transport and oxidative phosphorylation system. Annu. Rev. Biochem. 54, 1015-1069.
5. Fernie, A.R., Carrari, F. and Sweetlove, L.J. (2004) Respiratory metabolism: glycolysis, the TCA cycle and mitochondrial electron transport. Curr. Opin. Plant Biol. 7, 254-261.
6. Attardi, G. and Schatz, G. (1988) Biogenesis of mitochondria. Annu. Rev. Cell Biol. 4, 289-333.
7. Rich, P.R. (2003) The molecular machinery of Keilin's respiratory chain. Biochem. Soc. Trans. 31, 1095-1105.
8. Senior, A.E., Nadanaciva, S. and Weber, J. (2002) The molecular mechanism of ATP synthesis by F1F0-ATP synthase. Biochim. Biophys. Acta 1553, 188-211.
9. Wei, Y.H., Scholes, C.P. and King, T.E. (1981) Ubisemiquinone radicals from the cytochrome b-c1 complex of the mitochondrial electron transport chain--demonstration of QP-S radical formation. Biochem. Biophys. Res. Commun. 99, 1411-1419.
10. Boveris, A. and Chance, B. (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem. J. 134, 707-716.
11. Chance, B., Sies, H. and Boveris, A. (1979) Hydroperoxide metabolism in mammalian organs. Physiol. Rev. 59, 527-605.
12. Golden, T.R. and Melov, S. (2001) Mitochondrial DNA mutations, oxidative stress, and aging. Mech. Ageing Dev. 122, 1577-1589.
13. Benov, L. (2001) How superoxide radical damages the cell. Protoplasma 217, 33-36.
14. Koppenol, W.H. (2001) The Haber-Weiss cycle--70 years later. Redox Rep. 6, 229-234.
15. Alvarez, M.N., Trujillo, M. and Radi, R. (2002) Peroxynitrite formation from biochemical and cellular fluxes of nitric oxide and superoxide. Methods Enzymol. 359, 353-366.
16. Mladenka, P., Simunek, T., Hubl, M. and Hrdina, R. (2006) The role of reactive oxygen and nitrogen species in cellular iron metabolism. Free Radic. Res. 40, 263-272.
17. Nohl, H. and Hegner, D. (1978) Do mitochondria produce oxygen radicals in vivo? Eur. J. Biochem. 82, 563-567.
18. Shigenaga, M.K., Hagen, T.M. and Ames, B.N. (1994) Oxidative damage and mitochondrial decay in aging. Proc. Natl. Acad. Sci. USA 91, 10771-10778.
19. Sohal, R.S. and Dubey, A. (1994) Mitochondrial oxidative damage, hydrogen peroxide release, and aging. Free Radic. Biol. Med. 16, 621-626.
20. Gutteridge, J.M. (1992) Ageing and free radicals. Med. Lab. Sci. 49, 313-318.
21. Cristiano, F., de Haan, J.B., Iannello, R.C. and Kola, I. (1995) Changes in the levels of enzymes which modulate the antioxidant balance occur during aging and correlate with cellular damage. Mech. Ageing Dev. 80, 93-105.
22. Clayton, D.A. (1982) Replication of animal mitochondrial DNA. Cell 28, 693-705.
23. Driggers, W.J., Grishko, V.I., LeDoux, S.P. and Wilson, G.L. (1996) Defective repair of oxidative damage in the mitochondrial DNA of a xeroderma pigmentosum group A cell line. Cancer Res. 56, 1262-1266.
24. Shadel, G.S. and Clayton, D.A. (1997) Mitochondrial DNA maintenance in vertebrates. Annu. Rev. Biochem. 66, 409-435.
25. Wallace, D.C., Ye, J.H., Neckelmann, S.N., Singh, G., Webster, K.A. and Greenberg, B.D. (1987) Sequence analysis of cDNAs for the human and bovine ATP synthase beta subunit: mitochondrial DNA genes sustain seventeen times more mutations. Curr. Genet. 12, 81-90.
26. Richter, C. (1988) Do mitochondrial DNA fragments promote cancer and aging? FEBS Lett. 241, 1-5.
27. Ames, B.N., Shigenaga, M.K. and Hagen, T.M. (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl. Acad. Sci. USA 90, 7915-7922.
28. Agarwal, S. and Sohal, R.S. (1994) DNA oxidative damage and life expectancy in houseflies. Proc. Natl. Acad. Sci. USA 91, 12332-12335.
29. Siems, W., Quast, S., Carluccio, F., Wiswedel, I., Hirsch, D., Augustin, W., Hampi, H., Riehle, M. and Sommerburg, O. (2002) Oxidative stress in chronic renal failure as a cardiovascular risk factor. Clin. Nephrol. 58 Suppl 1, S12-S19.
30. Hagopian, K., Harper, M.E., Ram, J.J., Humble, S.J., Weindruch, R. and Ramsey, J.J. (2005) Long-term calorie restriction reduces proton leak and hydrogen peroxide production in liver mitochondria. Am. J. Physiol. Endocrinol. Metab. 288, E674-E684.
31. Bottje, W., Pumford, N.R., Ojano-Dirain, C., Iqbal, M. and Lassiter, K. (2006) Feed efficiency and mitochondrial function. Poult. Sci. 85, 8-14.
32. Ray, G. and Husain, S.A. (2002) Oxidants, antioxidants and carcinogenesis. Indian J. Exp. Biol. 40, 1213-1232.
33. Meister, A. (1984) New aspects of glutathione biochemistry and transport: selective alteration of glutathione metabolism. Fed. Proc. 43, 3031-3042.
34. Littarru, G.P. and Tiano, L. (2005) Clinical aspects of coenzyme Q10: an update. Curr. Opin. Clin. Nutr. Metab. Care 8, 641-646.
35. Zelko, I.N., Mariani, T.J. and Folz, R.J. (2002) Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic. Biol. Med. 33, 337-349.
36. Hutchison, C.A., III, Newbold, J.E., Potter, S.S. and Edgell, M.H. (1974) Maternal inheritance of mammalian mitochondrial DNA. Nature 251, 536-538.
37. Giles, R.E., Blanc, H., Cann, H.M. and Wallace, D.C. (1980) Maternal inheritance of human mitochondrial DNA. Proc. Natl. Acad. Sci. USA 77, 6715-6719.
38. Bogenhagen, D. and Clayton, D.A. (1974) The number of mitochondrial deoxyribonucleic acid genomes in mouse L and human HeLa cells. Quantitative isolation of mitochondrial deoxyribonucleic acid. J. Biol. Chem. 249, 7991-7995.
39. Anderson, S., Bankier, A.T., Barrell, B.G., de Bruijn, M.H., Coulson, A.R., Drouin, J., Eperon, I.C., Nierlich, D.P., Roe, B.A., Sanger, F. et al. (1981) Sequence and organization of the human mitochondrial genome. Nature 290, 457-465.
40. Fernandez-Silva, P., Enriquez, J.A. and Montoya, J. (2003) Replication and transcription of mammalian mitochondrial DNA. Exp. Physiol. 88, 41-56.
41. Fosslien, E. (2003) Review: Mitochondrial medicine--cardiomyopathy caused by defective oxidative phosphorylation. Ann. Clin. Lab. Sci. 33, 371-395.
42. Clayton, D.A. (2000) Transcription and replication of mitochondrial DNA. Hum. Reprod. 15 Suppl 2, 11-17.
43. Sazer, S. and Sherwood, S.W. (1990) Mitochondrial growth and DNA synthesis occur in the absence of nuclear DNA replication in fission yeast. J. Cell Sci. 97, 509-516.
44. Scarpulla, R.C. (1997) Nuclear control of respiratory chain expression in mammalian cells. J. Bioenerg. Biomembr. 29, 109-119.
45. Scarpulla, R.C. (2002) Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim. Biophys. Acta 1576, 1-14.
46. Lin, J., Puigserver, P., Donovan, J., Tarr, P. and Spiegelman, B.M. (2002) Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta ), a novel PGC-1-related transcription coactivator associated with host cell factor. J. Biol. Chem. 277, 1645-1648.
47. Puigserver, P. and Spiegelman, B.M. (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr. Rev. 24, 78-90.
48. Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R.C. et al. (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115-124.
49. Fridlender, B., Fry, M., Bolden, A. and Weissbach, A. (1972) A new synthetic RNA-dependent DNA polymerase from human tissue culture cells (HeLa-fibroblast-synthetic oligonucleotides-template-purified enzymes). Proc. Natl. Acad. Sci. USA 69, 452-455.
50. Huber, H.E., Tabor, S. and Richardson, C.C. (1987) Escherichia coli thioredoxin stabilizes complexes of bacteriophage T7 DNA polymerase and primed templates. J. Biol. Chem. 262, 16224-16232.
51. Ye, F., Carrodeguas, J.A. and Bogenhagen, D.F. (1996) The gamma subfamily of DNA polymerases: cloning of a developmentally regulated cDNA encoding Xenopus laevis mitochondrial DNA polymerase gamma. Nucleic Acids Res. 24, 1481-1488.
52. Lecrenier, N., Van Der, B.P. and Foury, F. (1997) Mitochondrial DNA polymerases from yeast to man: a new family of polymerases. Gene 185, 147-152.
53. Gray, H. and Wong, T.W. (1992) Purification and identification of subunit structure of the human mitochondrial DNA polymerase. J. Biol. Chem. 267, 5835-5841.
54. Lim, S.E., Longley, M.J. and Copeland, W.C. (1999) The mitochondrial p55 accessory subunit of human DNA polymerase gamma enhances DNA binding, promotes processive DNA synthesis, and confers N-ethylmaleimide resistance. J. Biol. Chem. 274, 38197-38203.
55. Johnson, A.A., Tsai, Y., Graves, S.W. and Johnson, K.A. (2000) Human mitochondrial DNA polymerase holoenzyme: reconstitution and characterization. Biochemistry 39, 1702-1708.
56. Longley, M.J., Prasad, R., Srivastava, D.K., Wilson, S.H. and Copeland, W.C. (1998) Identification of 5'-deoxyribose phosphate lyase activity in human DNA polymerase gamma and its role in mitochondrial base excision repair in vitro. Proc. Natl. Acad. Sci. USA 95, 12244-12248.
57. Ropp, P.A. and Copeland, W.C. (1996) Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics 36, 449-458.
58. Fan, L. and Kaguni, L.S. (2001) Multiple regions of subunit interaction in Drosophila mitochondrial DNA polymerase: three functional domains in the accessory subunit. Biochemistry 40, 4780-4791.
59. Fan, L., Sanschagrin, P.C., Kaguni, L.S. and Kuhn, L.A. (1999) The accessory subunit of mtDNA polymerase shares structural homology with aminoacyl-tRNA synthetases: implications for a dual role as a primer recognition factor and processivity clamp. Proc. Natl. Acad. Sci. USA 96, 9527-9532.
60. Carrodeguas, J.A., Pinz, K.G. and Bogenhagen, D.F. (2002) DNA binding properties of human pol gammaB. J. Biol. Chem. 277, 50008-50014.
61. Van, G.G., Dermaut, B., Lofgren, A., Martin, J.J. and Van, B.C. (2001) Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat. Genet. 28, 211-212.
62. Lamantea, E., Tiranti, V., Bordoni, A., Toscano, A., Bono, F., Servidei, S., Papadimitriou, A., Spelbrink, H., Silvestri, L., Casari, G. et al. (2002) Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. Ann. Neurol. 52, 211-219.
63. Longley, M.J., Clark, S., Yu Wai, M.C., Hudson, G., Durham, S.E., Taylor, R.W., Nightingale, S., Turnbull, D.M., Copeland, W.C. and Chinnery, P.F. (2006) Mutant POLG2 Disrupts DNA Polymerase gamma Subunits and Causes Progressive External Ophthalmoplegia. Am. J. Hum. Genet. 78, 1026-1034.
64. Nguyen, K.V., Ostergaard, E., Ravn, S.H., Balslev, T., Danielsen, E.R., Vardag, A., McKiernan, P.J., Gray, G. and Naviaux, R.K. (2005) POLG mutations in Alpers syndrome. Neurology 65, 1493-1495.
65. Naviaux, R.K. and Nguyen, K.V. (2005) POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. Ann. Neurol. 58, 491.
66. Ferrari, G., Lamantea, E., Donati, A., Filosto, M., Briem, E., Carrara, F., Parini, R., Simonati, A., Santer, R. and Zeviani, M. (2005) Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain 128, 723-731.
67. Rovio, A.T., Marchington, D.R., Donat, S., Schuppe, H.C., Abel, J., Fritsche, E., Elliott, D.J., Laippala, P., Ahola, A.L., McNay, D. et al. (2001) Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat. Genet. 29, 261-262.
68. Luoma, P., Melberg, A., Rinne, J.O., Kaukonen, J.A., Nupponen, N.N., Chalmers, R.M., Oldfors, A., Rautakorpi, I., Peltonen, L., Majamaa, K. et al. (2004) Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364, 875-882.
69. Graziewicz, M.A., Longley, M.J., Bienstock, R.J., Zeviani, M. and Copeland, W.C. (2004) Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. Nat. Struct. Mol. Biol. 11, 770-776.
70. Wanrooij, S., Luoma, P., van, G.G., van, B.C., Suomalainen, A. and Spelbrink, J.N. (2004) Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA. Nucleic Acids Res. 32, 3053-3064.
71. Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J.N., Rovio, A.T., Bruder, C.E., Bohlooly, Y., Gidlof, S., Oldfors, A., Wibom, R. et al. (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417-423.
72. Pinz, K.G., Shibutani, S. and Bogenhagen, D.F. (1995) Action of mitochondrial DNA polymerase gamma at sites of base loss or oxidative damage. J. Biol. Chem. 270, 9202-9206.
73. Graziewicz, M.A., Day, B.J. and Copeland, W.C. (2002) The mitochondrial DNA polymerase as a target of oxidative damage. Nucleic Acids Res. 30, 2817-2824.
74. Ogihara, M., Tanno, M., Izumiyama, N., Nakamura, H. and Taguchi, T. (2002) Increase in DNA polymerase gamma in the hearts of adriamycin-administered rats. Exp. Mol. Pathol. 73, 234-241.
75. Suliman, H.B., Welty-Wolf, K.E., Carraway, M., Tatro, L. and Piantadosi, C.A. (2004) Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis. Cardiovasc. Res. 64, 279-288.
76. Cortina, M.S., Gordon, W.C., Lukiw, W.J. and Bazan, N.G. (2005) Oxidative stress-induced retinal damage up-regulates DNA polymerase gamma and 8-oxoguanine-DNA-glycosylase in photoreceptor synaptic mitochondria. Exp. Eye Res. 81, 742-750.
77. DiMauro, S. and Moraes, C.T. (1993) Mitochondrial encephalomyopathies. Arch. Neurol. 50, 1197-1208.
78. Poulton, J. (1998) Mitochondrial gene mutations. Eur. J. Paediatr. Neurol. 2, 99-103.
79. Lestienne, P. and Bataille, N. (1994) Mitochondrial DNA alterations and genetic diseases: a review. Biomed. Pharmacother. 48, 199-214.
80. Wei, Y.H. and Lee, H.C. (2003) Mitochondrial DNA mutations and oxidative stress in mitochondrial diseases. Adv. Clin. Chem. 37, 83-128.
81. DiMauro, S. (2004) Mitochondrial diseases. Biochim. Biophys. Acta 1658, 80-88.
82. Wallace, D. C. (1999) Mitochondrial diseases in man and mouse. Science 283, 1482-1488.
83. Hauswirth, W.W. and Laipis, P.J. (1982) Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows. Proc. Natl. Acad. Sci. USA 79, 4686-4690.
84. Zeviani, M., Bertagnolio, B. and Uziel, G. (1996) Neurological presentations of mitochondrial diseases. J. Inherit. Metab Dis. 19, 504-520.
85. Chomyn, A., Martinuzzi, A., Yoneda, M., Daga, A., Hurko, O., Johns, D., Lai, S.T., Nonaka, I., Angelini, C. and Attardi, G. (1992) MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc. Natl. Acad. Sci. USA 89, 4221-4225.
86. Morris, A.A., Leonard, J.V., Brown, G.K., Bidouki, S.K., Bindoff, L.A., Woodward, C.E., Harding, A.E., Lake, B.D., Harding, B.N., Farrell, M.A. et al. (1996) Deficiency of respiratory chain complex I is a common cause of Leigh disease. Ann. Neurol. 40, 25-30.
87. Shoffner, J.M., Lott, M.T. and Wallace, D.C. (1991) MERRF: a model disease for understanding the principles of mitochondrial genetics. Rev. Neurol. (Paris) 147, 431-435.
88. Chomyn, A. (1998) The myoclonic epilepsy and ragged-red fiber mutation provides new insights into human mitochondrial function and genetics. Am. J. Hum. Genet. 62, 745-751.
89. Enriquez, J.A., Chomyn, A. and Attardi, G. (1995) MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNA(Lys) and premature translation termination. Nat. Genet. 10, 47-55.
90. Wallace, D.C., Zheng, X.X., Lott, M.T., Shoffner, J.M., Hodge, J.A., Kelley, R.I., Epstein, C.M. and Hopkins, L.C. (1988) Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell 55, 601-610.
91. Yasukawa, T., Suzuki, T., Ishii, N., Ohta, S. and Watanabe, K. (2001) Wobble modification defect in tRNA disturbs codon-anticodon interaction in a mitochondrial disease. EMBO J. 20, 4794-4802.
92. Hanna, M.G., Nelson, I.P., Morgan-Hughes, J.A. and Harding, A.E. (1995) Impaired mitochondrial translation in human myoblasts harbouring the mitochondrial DNA tRNA lysine 8344 A�蛄 (MERRF) mutation: relationship to proportion of mutant mitochondrial DNA. J. Neurol. Sci. 130, 154-160.
93. James, A.M., Wei, Y.H., Pang, C.Y. and Murphy, M.P. (1996) Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations. Biochem. J. 318, 401-407.
94. James, A.M., Sheard, P.W., Wei, Y.H. and Murphy, M.P. (1999) Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations. Eur. J. Biochem. 259, 462-469.
95. Antonicka, H., Floryk, D., Klement, P., Stratilova, L., Hermanska, J., Houstkova, H., Kalous, M., Drahota, Z., Zeman, J. and Houstek, J. (1999) Defective kinetics of cytochrome c oxidase and alteration of mitochondrial membrane potential in fibroblasts and cytoplasmic hybrid cells with the mutation for myoclonus epilepsy with ragged-red fibres ('MERRF') at position 8344 nt. Biochem. J. 342 Pt 3, 537-544.
96. Ide, T., Tsutsui, H., Kinugawa, S., Utsumi, H., Kang, D., Hattori, N., Uchida, K., Arimura, K., Egashira, K. and Takeshita, A. (1999) Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ. Res. 85, 357-363.
97. Ide, T., Tsutsui, H., Hayashidani, S., Kang, D., Suematsu, N., Nakamura, K., Utsumi, H., Hamasaki, N. and Takeshita, A. (2001) Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ. Res. 88, 529-535.
98. Trifunovic, A., Hansson, A., Wredenberg, A., Rovio, A.T., Dufour, E., Khvorostov, I., Spelbrink, J.N., Wibom, R., Jacobs, H.T. and Larsson, N.G. (2005) Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl. Acad. Sci. USA 102, 17993-17998.
99. Stuart, J.A. and Brown, M.F. (2006) Mitochondrial DNA maintenance and bioenergetics. Biochim. Biophys. Acta 1757, 79-89.
100. Barrientos, A., Casademont, J., Cardellach, F., Ardite, E., Estivill, X., Urbano-Marquez, A., Fernandez-Checa, J.C. and Nunes, V. (1997) Qualitative and quantitative changes in skeletal muscle mtDNA and expression of mitochondrial-encoded genes in the human aging process. Biochem. Mol. Med. 62, 165-171.
101. Barrientos, A., Casademont, J., Cardellach, F., Estivill, X., Urbano-Marquez, A. and Nunes, V. (1997) Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging. Brain Res. Mol. Brain Res. 52, 284-289.
102. Lee, H.C., Lu, C.Y., Fahn, H.J. and Wei, Y.H. (1998) Aging- and smoking-associated alteration in the relative content of mitochondrial DNA in human lung. FEBS Lett. 441, 292-296.
103. Masuyama, M., Iida, R., Takatsuka, H., Yasuda, T. and Matsuki, T. (2005) Quantitative change in mitochondrial DNA content in various mouse tissues during aging. Biochim. Biophys. Acta 1723, 302-308.
104. Liu, C.S., Tsai, C.S., Kuo, C.L., Chen, H.W., Lii, C.K., Ma, Y.S. and Wei, Y.H. (2003) Oxidative stress-related alteration of the copy number of mitochondrial DNA in human leukocytes. Free Radic. Res. 37, 1307-1317.
105. Liu, C.S., Chen, Y.Y., Cheng, W.L., Tsai, C.S., Lee, C.F., Ma, Y.S., Lin, C.Y., Huang, C.C. and Wei, Y.H. (2006) Alteration in the copy number of mitochondrial DNA in leukocytes of patients with mitochondrial encephalomyopathies. Acta Neurol. Scand. 113, 334-351.
106. Chen, D., Cao, G., Hastings, T., Feng, Y., Pei, W., O'Horo, C. and Chen, J. (2002) Age-dependent decline of DNA repair activity for oxidative lesions in rat brain mitochondria. J. Neurochem. 81, 1273-1284.
107. von Wurmb-Schwark, N., Higuchi, R., Fenech, A.P., Elfstroem, C., Meissner, C., Oehmichen, M. and Cortopassi, G.A. (2002) Quantification of human mitochondrial DNA in a real time PCR. Forensic Sci. Int. 126, 34-39.
108. Davies, K.J.A. (1999) The broad spectrum of responses to oxidants in proliferating cells: a new paradigm for oxidative stress. IUBMB Life 48, 41-47.
109. Nath, K.A., Enright, H., Nutter, L., Fischereder, M., Zou, J.N. and Hebbel, R.P. (1994) Effect of pyruvate on oxidant injury to isolated and cellular DNA. Kidney Int. 45, 166-176.
110. Mambo, E., Gao, X., Cohen, Y., Guo, Z., Talalay, P. and Sidransky, D. (2003) Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations. Proc. Natl. Acad. Sci. USA 100, 1838-1843.
111. Cooper, J.M., Mann, V.M. and Schapira, A.H. (1992) Analyses of mitochondrial respiratory chain function and mitochondrial DNA deletion in human skeletal muscle: effect of ageing. J. Neurol. Sci. 113, 91-98.
112. Schapira, A.H. and Cooper, J.M. (1992) Mitochondrial function in neurodegeneration and ageing. Mutat. Res. 275, 133-143.
113. Lee, H.C. and Wei, Y.H. (1997) Role of mitochondria in human aging. J. Biomed. Sci. 4, 319-326.
114. DiMauro, S., Bonilla, E., Davidson, M., Hirano, M. and Schon, E.A. (1998) Mitochondria in neuromuscular disorders. Biochim. Biophys. Acta 1366, 199-210.
115. Wei, Y.H., Lu, C.Y., Wei, C.Y., Ma, Y.S. and Lee, H.C. (2001) Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system. Chin. J. Physiol 44, 1-11.
116. Lee, H.C. and Wei, Y.H. (2001) Mitochondrial alterations, cellular response to oxidative stress and defective degradation of proteins in aging. Biogerontology 2, 231-244.
117. McKenzie, M., Liolitsa, D. and Hanna, M.G. (2004) Mitochondrial disease: mutations and mechanisms. Neurochem. Res. 29, 589-600.
118. Lu, C.Y., Wang, E.K., Lee, H.C., Tsay, H.J. and Wei, Y.H. (2003) Increased expression of manganese-superoxide dismutase in fibroblasts of patients with CPEO syndrome. Mol. Genet. Metab. 80, 321-329.
119. Lee, C.F., Chen, Y.C., Liu, C.Y. and Wei, Y.H. (2006) Involvement of protein kinase C delta in the alteration of mitochondrial mass in human cells under oxidative stress. Free Radic. Biol. Med. 40, 2136-2146.
120. Lee, H.C., Yin, P.H., Lu, C.Y., Chi, C.W. and Wei, Y.H. (2000) Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells. Biochem. J. 348, 425-432.
121. Wei, Y.H., Lee, C.F., Lee, H.C., Ma, Y.S., Wang, C.W., Lu, C.Y. and Pang, C.Y. (2001) Increases of mitochondrial mass and mitochondrial genome in association with enhanced oxidative stress in human cells harboring 4,977 bp-deleted mitochondrial DNA. Ann. N.Y. Acad. Sci. 928, 97-112.
122. Lee, H.C., Yin, P.H., Chi, C.W. and Wei, Y.H. (2002) Increase in mitochondrial mass in human fibroblasts under oxidative stress and during replicative cell senescence. J. Biomed. Sci., 9, 517-526.
123. Lee, C.F., Liu, C.Y., Hsieh, R.H. and Wei, Y.H. (2005) Oxidative stress-induced depolymerization of microtubules and alteration of mitochondrial mass in human cells. Ann. N.Y. Acad. Sci. 1042, 246-254.
124. Doudican, N.A., Song, B., Shadel, G.S. and Doetsch, P.W. (2005) Oxidative DNA damage causes mitochondrial genomic instability in Saccharomyces cerevisiae. Mol. Cell Biol. 25, 5196-5204.
125. Banmeyer, I., Marchand, C., Clippe, A. and Knoops, B. (2005) Human mitochondrial peroxiredoxin 5 protects from mitochondrial DNA damages induced by hydrogen peroxide. FEBS Lett. 579, 2327-2333.
126. Mandavilli, B.S., Boldogh, I. and Van, H.B. (2005) 3-nitropropionic acid-induced hydrogen peroxide, mitochondrial DNA damage, and cell death are attenuated by Bcl-2 overexpression in PC12 cells. Brain Res. Mol. Brain Res. 133, 215-223.
127. Suematsu, N., Tsutsui, H., Wen, J., Kang, D., Ikeuchi, M., Ide, T., Hayashidani, S., Shiomi, T., Kubota, T., Hamasaki, N. et al. (2003) Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 107, 1418-1423.
128. Wenk, J., Brenneisen, P., Wlaschek, M., Poswig, A., Briviba, K., Oberley, T.D. and Scharffetter-Kochanek, K. (1999) Stable overexpression of manganese superoxide dismutase in mitochondria identifies hydrogen peroxide as a major oxidant in the AP-1-mediated induction of matrix-degrading metalloprotease-1. J. Biol. Chem. 274, 25869-25876.
129. van Houten, B., Cheng, S. and Chen, Y. (2000) Measuring gene-specific nucleotide excision repair in human cells using quantitative amplification of long targets from nanogram quantities of DNA. Mutat. Res. 460, 81-94.
130. Santos, J.H., Mandavilli, B.S. and van Houten, B. (2002) Measuring oxidative mtDNA damage and repair using quantitative PCR. Methods Mol. Biol. 197, 159-176.
131. Lin, P.H., Lee, S.H., Su, C.P. and Wei, Y.H. (2003) Oxidative damage to mitochondrial DNA in atrial muscle of patients with atrial fibrillation. Free Radic. Biol. Med. 35, 1310-1318.
132. Ali, M.H., Schlidt, S.A., Chandel, N.S., Hynes, K.L., Schumacker, P.T. and Gewertz, B.L. (1999) Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction. Am. J. Physiol 277, L1057-L1065.
133. Takano, H., Zou, Y., Hasegawa, H., Akazawa, H., Nagai, T. and Komuro, I. (2003) Oxidative stress-induced signal transduction pathways in cardiac myocytes: involvement of ROS in heart diseases. Antioxid. Redox. Signal. 5, 789-794.
134. Chen, K., Thomas, S.R. and Keaney, J.F., Jr. (2003) Beyond LDL oxidation: ROS in vascular signal transduction. Free Radic. Biol. Med. 35, 117-132.
135. de Souza, G.A., Godoy, L.M., Teixeira, V.R., Otake, A.H., Sabino, A., Rosa, J.C., Dinarte, A.R., Pinheiro, D.G., Silva, W.A., Jr., Eberlin, M.N. et al. (2006) Proteomic and SAGE profiling of murine melanoma progression indicates the reduction of proteins responsible for ROS degradation. Proteomics 6, 1460-1470.
136. Takamatsu, C., Umeda, S., Ohsato, T., Ohno, T., Abe, Y., Fukuoh, A., Shinagawa, H., Hamasaki, N. and Kang, D. (2002) Regulation of mitochondrial D-loops by transcription factor A and single-stranded DNA-binding protein. EMBO Rep. 3, 451-456.
137. Ghivizzani, S.C., Madsen, C.S., Nelen, M.R., Ammini, C.V. and Hauswirth, W.W. (1994) In organello footprint analysis of human mitochondrial DNA: human mitochondrial transcription factor A interactions at the origin of replication. Mol. Cell Biol. 14, 7717-7730.
138. de Grey, A.D. (2005) Reactive oxygen species production in the mitochondrial matrix: implications for the mechanism of mitochondrial mutation accumulation. Rejuvenation Res. 8, 13-17.
139. Ma, Y.S., Chen, Y.C., Lu, C.Y., Liu, C.Y. and Wei, Y.H. (2005) Upregulation of matrix metalloproteinase 1 and disruption of mitochondrial network in skin fibroblasts of patients with MERRF syndrome. Ann. N.Y. Acad. Sci. 1042, 55-63.
140. Lu, C.Y., Lee, H.C., Fahn, H.J. and Wei, Y.H. (1999) Oxidative damage elicited by imbalance of free radical scavenging enzymes is associated with large-scale mtDNA deletions in aging human skin. Mutat. Res. 423, 11-21.
141. Ohkoshi, N., Mizusawa, H., Shiraiwa, N., Shoji, S., Harada, K. and Yoshizawa, K. (1995) Superoxide dismutases of muscle in mitochondrial encephalomyopathies. Muscle Nerve 18, 1265-1271.
142. Mitsui, T., Kawai, H., Nagasawa, M., Kunishige, M., Akaike, M., Kimura, Y. and Saito, S. (1996) Oxidative damage to skeletal muscle DNA from patients with mitochondrial encephalomyopathies. J. Neurol. Sci. 139, 111-116.
143. Kirkinezos, I.G. and Moraes, C.T. (2001) Reactive oxygen species and mitochondrial diseases. Semin. Cell Dev. Biol. 12, 449-457.
144. Filosto, M., Tonin, P., Vattemi, G., Spagnolo, M., Rizzuto, N. and Tomelleri, G. (2002) Antioxidant agents have a different expression pattern in muscle fibers of patients with mitochondrial diseases. Acta Neuropathol. 103, 215-220.
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