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研究生(中)周宜芳
研究生(英)Yi-Fang Chou
論文名稱(中)葉酸缺乏促進年輕大鼠組織老化指標粒線體DNA大片段斷損累積及其相關機制
論文名稱(英)Folate depletion promotes mtDNA premature aging in lymphocytes and various tissues of young rats, which is associated with mtDNA biogenesis and elevated oxidative stress
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指導教授(中)許瑞芬
指導教授(英)Rewi-Fen Shu Huang
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關鍵字(中)葉酸 mtDNA大片段斷損 mtDNA拷貝數 8-OHdG 同半胱胺酸
關鍵字(英)Folate Homocysteine 8-OHdG ΔmtDNA4.8kb mtDNA content
摘要(中)哺乳動物老化組織中常有氧化傷害相關的粒線體DNA大片段斷損的累積,且此斷損為老化的分子生物指標。研究指出葉酸缺乏會使年老鼠之肝臟粒線體DNA 4.8 kb大片段斷損 (ΔmtDNA4.8 kb) 顯著增加,若補充則可以降低斷損累積。然而葉酸營養不良是否促進年輕大鼠此斷損的累積及可能機制目前未明。本研究以動物模式,投予雄性Wistar初離乳大鼠葉酸缺乏 (0 mg/kg diet) 與葉酸對照 (8 mg/kg diet) 飲食,收集血液及各組織 (心、肝、肺、腎、胰、腦、脾、肌、胃及小腸),以微生物法分析葉酸含量;以螢光偏極免疫法檢測血漿同半胱胺酸濃度;利用高效能液相層析法測定組織中8-hydroxy-2’-deoxyquanosine (8-OHdG) 含量;最後以即時定量聚合?連鎖反應檢測mtDNA拷貝數及ΔmtDNA4.8 kb相對量。結果顯示隨著葉酸缺乏的時間增加,動物之血液、淋巴球及各組織臟器之葉酸濃度皆顯著低於對照組,而血漿同半胱胺酸濃度顯著增加顯示葉酸缺乏動物體內呈現氧化壓力增加的情形。ΔmtDNA4.8kb測定結果中,兩週葉酸缺乏動物只有胃臟及胰臟之ΔmtDNA4.8 kb顯著增加,而到葉酸缺乏第四週時,動物淋巴球及70%組織 (心、肝、胰、腦、脾、肌肉及胃) 之ΔmtDNA4.8 kb有顯著累積。mtDNA拷貝數於葉酸缺乏二週時,動物的淋巴球與脾組織皆顯著下降,到四週葉酸缺乏時動物的淋巴球及四個組織 (心、肝、肌肉及脾) 之mtDNA拷貝數則皆顯著增加。同時,兩週與四週葉酸缺乏組的粒線體葉酸量皆與ΔmtDNA4.8kb呈顯著負相關性,因此斷損的累積可能與葉酸缺乏所造成的氧化壓力有關。於四週葉酸缺乏動物的mtDNA拷貝數與細胞質及粒線體的葉酸量皆呈顯著負相關,顯示除了粒線體的葉酸量可能會影響mtDNA的生合成外,細胞質的葉酸也可能參與了mtDNA拷貝數的複製。四週葉酸缺乏之年輕鼠ΔmtDNA4.8kb含量與mtDNA拷貝數呈顯著正相關,但對照組動物並無此現象。此外,肝組織內DNA氧化傷害指標8-OHdG與肝臟ΔmtDNA4.8kb及血漿同半胱胺酸濃度皆呈顯著正相關。淋巴球ΔmtDNA4.8kb與70%組織器官內ΔmtDNA4.8kb呈顯著正相關性,顯示淋巴球ΔmtDNA4.8kb累積能夠反應動物組織器官間ΔmtDNA4.8kb的堆積程度。綜合上述,葉酸營養不良促進年輕動物體內淋巴球及各組織器官ΔmtDNA4.8kb的累積,且隨著葉酸缺乏動物mtDNA拷貝數增加,此ㄧ老化指標可能有隨之增生的情形,並可能與葉酸缺乏所促進的氧化壓力有關。而淋巴球ΔmtDNA4.8kb量可反應葉酸缺乏動物體內mtDNA斷損程度,似乎可發展為評估營養不良促進老化程度的分子生物指標,其臨床應用性更待進一步研究。
摘要(英)Mitochondrial DNA large deletion is often accumulated in aging tissues of human and rodents. Previous studies have shown that mitochondrial DNA 4.8 kb common deletion (ΔmtDNA4.8kb) increased in the liver tissue of aging rats fed folate deficient diet, and folate supplementation reduced mtDNA large deletion level. The aim of the study is realize the mechanism of accumulated deletion in young rat with folate deficiency. Wistar weaning male rats were fed with control and folate deficient diet for 2- and 4-wks. Whole blood and ten tissues samples including heart, liver, lung, kidney, pancreas, brain, spleen, muscle, stomach and small intestine were collected after 2-or 4-wk FD feeding period. We examined folate concentration, plasma homocysteine (Hcy) content, DNA oxidative damage (8-hydroxy-2’- deoxyquanosine, 8-OHdG), mitochondrial DNA 4.8 kb common deletion (ΔmtDNA4.8kb) and mtDNA copy number in blood or each tissue. After a 2 and 4-wk feeding period, blood and tissue cytosolic as well as mitochondrial folate levels of the rats decreased significantly. Plasma Hcy concentrations of 4 wk folate-depleted rats increased significantly compared with those of control and 2 wk folate-depleted rats. By quantitative real time PCR, 4-wk FD group had significantly higher ΔmtDNA4.8kb level than control group in lymphocytes and eight tissues (heart, liver, pancreas, brain, spleen, muscle and stomach), the 4 wk FD group had higher mtDNA content than control group in lymphocytes and four tissues (heart, liver, muscle and spleen). For 2-or 4-wk FD group, ΔmtDNA4.8kb levels were significantly correlated with mitochondrial folate. MtDNA copy number was significant negative association with cytosolic and mitochondrial folate in 4-wk FD. Significant positive correlation between ΔmtDNA4.8kb and mtDNA copy number was observed for 4 wk FD animals, but not for control rats. The increase mtDNA biogenesis in folate-depleted rats appeared to be associated with increased oxidative stress as levels of 8-OHdG were significantly higher in 4 wk-FD rat liver than in control rat liver. A positive association between mtDNA damage in lymphocyte and ΔmtDNA4.8kb in 70% of tissues, suggesting that lymphocytes’ ΔmtDNA4.8kb may reflect the extent of mtDNA damage among tissues of rats. Taken together, our results demonstrated that folate deprivation accelerated mtDNA common deletion among lymphocytes and different tissues of young rats in mitochondrial folate-dependent matter. We supposed the mechanism of ΔmtDNA4.8kb accumulation could be increased via in replication of mtDNA copy number.
論文目次目錄 頁次 中文摘要…………………………………………………………. …….. II 英文摘要………………………………………………………….. ……. IV 致謝……………………………………………………………………… VI 表目錄…………………………………………………………….. ……. X 圖目錄…………………………………………………………….. ……. X 第一章 前言……………………………………………………………. 1 第二章 文獻回顧………………………………………………………. 3 一. 葉酸………………………….…………………………….. ……. 3 (一) 葉酸單碳代謝……….………………………………………. 2 (二) 葉酸的抗氧化特性……….…………………………………. 3 (三) 葉酸缺乏與氧化壓力的關係……….………………………. 3 (四) 葉酸營養不良對細胞核基因的影響….……………..……... 4 二、粒線體………………………….…………………………………. 4 (一) 粒線體生化功能性….………………………………………. 4 (二) 粒線體DNA基因特性….…………………………….. ……. 5 (三) 粒線體生合成….………………………………………. ……. 5 (四) 內生性氧化壓力來源 : 粒線體….…………………………. 6 (五) 粒線體DNA的突變的機制….……………………….. ……. 7 (六) 粒線體DNA大片段斷損與老化的關係……………………. 8 三、葉酸對粒線體基因的影響………….. …………………………. 9 四、本研究目標…………..…………..…………..……………. ……. 10 第三章 實驗材料與方法…………...…………..……………….. …… 11 一、實驗設計…..…………..…………..…………………………….. 11 二、實驗材料…..…………..…………..…………………………….. 11 (一) 實驗動物…..…………..…………..…………………………. 11 (二) 飼料…..…………..…………..………………………………. 11 三、分析項目與方法…..…………..…………..……………………. 11 (一) 分離血漿、血球及週邊血液淋巴球細胞……………. ……. 11 (二)、細胞質及粒線體的分離…..…………..…………..…. ……. 12 (三)、DNA之萃取…..…………..…………..…………………….. 12 (四)、PCR產物純化與基因定序…………………………………. 13 (五)、DNA之8-OHdG氧化傷害測定…………………….. ……. 14 (六)、即時定量聚合?反應 (real-time PCR)……………………. 14 1. MtDNA 4834 bp大片段斷損定量…………………….. ……. 14 2. MtDNA拷貝數定量…………………………………………. 14 3.引子及TaqMan探針的選擇…………………………………. 15 4. PCR反應條件………………………………………..... …….. 15 5. PCR反應溫度與時間………………………………….. ……. 15 (七)、葉酸含量分析………………………………………………... 15 1.葉酸的萃取……………………………………………………. 15 2.葉酸濃度測定…………………………………….. …………. 16 四、統計分析…………………………………….. …………………. 16 第四章 結果…………………………………….. ……….. …….. ……. 17 一、實驗動物生長情形……………………………………….. ……. 17 二、葉酸缺乏對大鼠血液葉酸、血漿Hcy含量、淋巴球葉酸及各組織葉酸濃度的影響……………..……...………………….….. 17 (一) 葉酸缺乏大鼠之血液葉酸濃度……………………….. ……. 17 (二) 葉酸缺乏大鼠之血漿Hcy含量………………………. ……. 17 (三) 葉酸缺乏大鼠之淋巴球葉酸濃度 17 (四)、葉酸缺乏大鼠各組織器官葉酸濃度………………………. 18 1.葉酸缺乏大鼠各組織器官均質液總葉酸含量……….. ……. 18 2.葉酸缺乏大鼠各組織器官細胞質葉酸含量…………………. 18 3.葉酸缺乏大鼠各組織器官粒線體葉酸含量…………………. 18 三、葉酸缺乏大鼠肝臟粒線體DNA斷損測定及斷損定序結果…. 19 四、葉酸缺乏對大鼠淋巴球及各臟器粒線體DNA斷損的影響…. 20 五、足量葉酸飲食對大鼠淋巴球及各臟器粒線體DNA斷損的影響. 20 六、葉酸缺乏對大鼠淋巴球及各臟器mtDNA拷貝數的影響……. 20 七、足量葉酸飲食對大鼠淋巴球及各臟器mtDNA拷貝數的影響.. 21 八、葉酸缺乏大鼠細胞組織均質液總葉酸濃度與ΔmtDNA4.8 kb的相關性………………………………….. …….. …….. ……….. 21 九、葉酸缺乏大鼠細胞組織細胞質葉酸濃度與ΔmtDNA4.8 kb的相關性………………………………….. …….. …….. ……. ……. 21 十、葉酸缺乏大鼠細胞組織粒線體葉酸濃度與ΔmtDNA4.8 kb的相關性………………………………….. …….. …….. ……. ……. 21 十一、葉酸缺乏大鼠血漿葉酸濃度與ΔmtDNA4.8 kb的相關性…… 22 十二、葉酸缺乏大鼠細胞組織均質液總葉酸濃度與mtDNA拷貝數的相關性………………………………….. …….. ……… 22 十三、葉酸缺乏大鼠細胞組織細胞質葉酸濃度與mtDNA拷貝數的相關性………………………………….. …….. ……. …… 22 十四、葉酸缺乏大鼠細胞組織粒線體葉酸濃度與mtDNA拷貝數的相關性………………………………….. …….. ……. …… 22 十五、大白鼠各組臟器ΔmtDNA4.8 kb與mtDNA拷貝數之相關…. 23 十六、葉酸缺乏對大鼠肝臟DNA氧化壓力8-OHdG的影響……. 23 十七、葉酸缺乏大鼠肝臟8-OHdG與葉酸濃度、血漿Hcy濃度之相關性………………………………………………………… 23 十八、葉酸缺乏大鼠肝臟8-OHdG與肝臟ΔmtDNA4.8 kb及肝臟mtDNA拷貝數之相關性…………………………………..… 24 十九、葉酸缺乏大鼠淋巴球葉酸濃度及淋巴球ΔmtDNA4.8 k b與各組織器官ΔmtDNA4.8 k b相關性……………………………… 24 二十、葉酸缺乏大鼠淋巴球ΔmtDNA4.8 k b與血液葉酸及血漿Hcy濃度的相關性………………………………………………… 24 二十一、葉酸缺乏大鼠葉酸濃度與ΔmtDNA4.8 k b的邏輯式回歸統計結果…………………………………..……...…………….. 24 第五章 討論…………………………………………………………….. 26 一、葉酸缺乏對大鼠體重的影響…………………………………… 26 二、葉酸缺乏對大鼠血液葉酸含量的影響………………………… 26 三、葉酸缺乏對大鼠血漿同半胱胺酸的影響…………………….. 26 四、葉酸缺乏對大鼠組織葉酸含量的影響……………………….. 27 五、葉酸缺乏對大鼠淋巴球及各臟器粒線體DNA斷損的影響…. 27 六、葉酸缺乏對大鼠淋巴球及各臟器mtDNA拷貝數的影響……. 28 七、足量葉酸飲食對大鼠淋巴球及各臟器ΔmtDNA4.8 kb及mtDNA拷貝數的影響…………………………………………………… 29 八、葉酸缺乏大鼠細胞組織之細胞質及粒線體中葉酸濃度的改變與ΔmtDNA4.8 kb含量的相關性………………………………… 29 九、葉酸缺乏大鼠細胞組織之細胞質及粒線體中葉酸濃度的改變與mtDNA拷貝數的相關性…………………………………… 30 十、大白鼠各組臟器ΔmtDNA4.8 kb與mtDNA拷貝數之相關性…. 30 十一、葉酸缺乏於大鼠肝臟8-OHdG的變化以及與血漿Hcy、ΔmtDNA4.8 kb及mtDNA拷貝數的關係……………………….. 31 十二、葉酸缺乏大鼠淋巴球之ΔmtDNA4.8 kb與淋巴球葉酸之相關性探討以及淋巴球於臨床上的重要性…………................... 32 第六章 結論……………………………………………………………. 33 參考文獻………………………………………………………………… 57 附表……………………………………………………………………… 73 表目錄 表一、 本實驗進行即時定量聚合?反應所使用之引子與TaqMan探針及其相對位置……………………………………………………… 35 表二、Wistar大白鼠攝取葉酸缺乏兩週及四週飲食各組織總葉酸濃度 38 表三、Wistar 大白鼠各組織細胞粒線體DNA斷損相對量…………… 44 表四、Wistar 大白鼠各組織細胞粒線體DNA拷貝數相對量………… 45 表五、Wistar大白鼠肝臟DNA氧化傷害指標8-OHdG與葉酸濃度、血漿同半胱胺酸、肝臟ΔmtDNA 4.8 kb及mtDNA拷貝數含量之相關性..... …………………………………………………………….. 56 表六、Wistar大白鼠淋巴球粒線體DNA斷損或淋巴球葉酸濃度與各組織細胞粒線體DNA斷損之相關性………………………………. 57 表七、Wistar大白鼠淋巴球ΔmtDNA 4.8 kb與血液葉酸及血漿同半胱胺 酸濃度之相關性…………………………………………………… 58 表八、Wistar大白鼠粒線體DNA斷損與細胞質及粒線體葉酸濃度之勝算比……………………………………………………………….. 59 圖目錄 圖一、Wistar大白鼠攝取葉酸缺乏與對照飲食二或四週後之體重變化... 36 圖二、Wistar大白鼠血液葉酸濃度及血漿中同半胱胺酸含量………… 37 圖三、Wistar大白鼠攝取葉酸缺乏兩週及四週飲食各組織細胞質及粒線體葉酸濃度……………………………………………………… 39 圖三(續)、Wistar大白鼠攝取葉酸缺乏兩週及四週飲食淋巴球及各組織細胞質及粒線體葉酸濃度……………………………………… 40 圖四、葉酸缺乏對大白鼠肝臟粒線體DNA大片段斷損的影響………. 41 圖五、Wistar大白鼠各組織細胞粒線體DNA斷損相對量…………….. 42 圖六、Wistar 大白鼠各組織細胞粒線體DNA拷貝數相對量…………. 43 圖七、Wistar大白鼠粒線體DNA斷損與總葉酸濃度的相關性………. 46 圖八、Wistar大白鼠粒線體DNA斷損與細胞質葉酸濃度的相關性…. 47 圖九、Wistar大白鼠粒線體DNA斷損與粒線體葉酸濃度的相關性….. 48 圖十、四週葉酸缺乏Wistar大白鼠粒線體DNA斷損與血漿葉酸濃度之相關性…………………………………………………………… 49 圖十一、Wistar大白鼠粒線體DNA拷貝數與總葉酸濃度的相關性…. 50 圖十二、Wistar大白鼠粒線體DNA拷貝數與細胞質葉酸濃度的相關性 51 圖十三、Wistar大白鼠粒線體DNA拷貝數與粒線體葉酸濃度的相關性 52 圖十四、Wistar大白鼠粒線體DNA斷損與粒線體DNA拷貝數相關性 53 圖十五、Wistar大白鼠標準品或肝臟DNA中8-OHdG及dG之波峰… 54 圖十六、Wistar大白鼠肝臟之DNA氧化傷害指標8-OHdG含量…….. 55
參考文獻余朱青 (2006) 葉酸調節肝臟粒線體呼吸酵素複體IV功能性及其機制探討 碩士論文 輔仁大學食品營養學系 張純敏 (2004) 葉酸營養狀態對大白鼠肝臟粒線體基因斷損,功能性及氧化傷害的影響 碩士論文 輔仁大學食品營養學系 盧信得(2003)粒線體葉酸代謝異常對粒線體功能性的影響 碩士論文 輔仁大學食品營養學系 Ahrendt SA and Sidransky D (1999) The potential of molecular screening. Surg Oncol Clin N Am 8: 641-656. Akbari M, Skjelbred C, Folling I, Sagen J and Krokan HE. (2004) A gel electrophoresis method for detection of mitochondrial DNA mutation (3243 tRNA(Leu (UUR))) applied to a Norwegian family with diabetes mellitus and hearing loss. Scand J Clin Lab Invest 64 : 86-92. Ames BN. (1999) Cancer prevention and diet: help from single nucleotide polymorphisms. Proc Natl Acad Sci USA 96 : 12216–12218. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R and Young IG. (1981) Sequence and organization of the human mitochondrial genome. Nature 290 : 457-65. Arnheim N. (1990) Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res 18 : 6927-6933. Attardi G, Yoneda M and Chomyn A. (1995) Complementation and segregation behavior of disease-causing mitochondrial DNA mutations in cellular model systems. Biochim Biophys Acta 1271 : 241-248. Babior BM and Woodman RC. (1990) Chronic granulomatous disease. Semin. Hematol. 27 : 247-259. Balaghi M, Horne DW and Wagner C. (1993) a Hepatic one-carbon metabolism in early folate deficiency in rats. Biochem J 291 : 145-149. Balaghi M and Wagner C (1993) b DNA methylation in folate deficiency: use of CpG methylase. Biochem Biophys Res Commun 193 : 1184-1190. Balaghi M, Horne D, Woodward S and Wagner C. (1993) c Pancreatic one-carbon metabolism in early folate deficiency in rats. Am J Clin Nutr 58 : 198-203. Barrientos A, Casademont J, Cardellach F, Estivill X, Urbano-Marquez A and Nunes V. (1997a). 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. Barrientos A, Casademont J, Cardellach F, Ardite E, Estivill X, Urbano-Marquez A, Fernandez-Checa JC and Nunes V. (1997b) 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. Berdanier CD and Everts HB. (2001) Mitochondrial DNA in aging and degenerative disease. Mutat Res 475 : 169-183. Bianchi MS, Bianchi NO and Bailliet G. (1995) Mitochondrial DNA mutations in normal and tumor tissues from breast cancer patients. Cytogenet. Cell Genet 71 : 99-103. Blasco C, Caballeria J, Deulofeu R, Lligona A, Pares A, Lluis JM, Gual A and Rodes J. (2005) Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics. Alcohol Clin Exp Res. 29 : 1044-1048. Biagini G, Pallotti F, Carraro S, Sgorbi G, Pich MM, Lenaz G, Anzivino F, Gualandi G and Xin D. (1998) Mitochondrial DNA in platelets from aged subjects. Mech. Ageing Dev. 101: 269-275. Blok RB, Thorburn DR, Thompson GN and Dahl HH. (1995) A topoisomerase II cleavage site is associated with a novel mitochondrial DNA deletion. Hum Genet. 95 : 75-81. Bohr VA and Dianov GL. (1999) Oxidative DNA damage processing in nuclear and mitochondrial DNA. Biochimie 81 : 155-160. Boffoli D, Scacco SC, Vergari R, Solarino G, Santacroce G and Papa S. (1994) Decline with age of the respiratory chain activity in human skeletal muscle. Biochim Biophys Acta 1226 : 73-82. Bradford MM. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72 : 248-54. Branda RF, O'Neill JP, Jacobson-Kram D and Albertini RJ. (1992) Factors influencing mutation at the hprt locus in T-lymphocytes: studies in normal women and women with benign and malignant breast masses. Environ Mol Mutagen 19 : 274-281. Branda RF, Brooks EM, Chen Z, Naud SJ and Nicklas JA. (2002) Dietary modulation of mitochondrial DNA deletions and copy number after chemotherapy in rats. Mutat Res. 501 : 29-36. Brookes PS and Baggott(2002) Oxidation of 10-formyltetrahydrofolate to 10-formyldihydrofolate by complex Ⅳ of rat mitochondria. Biochem 41:5633-5636. Bohr VA and Dianov GL. (1999) Oxidative DNA damage processing in nuclear and mitochondrial DNA. Biochimie 81 : 155-160. Bosy-Westphal A, Petersen S, Hinrichsen H, Czech N and J Muller M. (2001) Increased plasma homocysteine in liver cirrhosis. Hepatol Res. 20 : 28-38. Burdon RH. (1995) Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Rad Biol Medicine 18 : 775-794. Crott JW, Choi SW, Branda RF and Mason JB. (2005) Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats. Mutat Res. 570 : 63-70. Ceranic B and Luxon LM. (2004) Progressive auditory neuropathy in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 75 : 626-630. Chance B, Sies H and Boveris A. (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59 : 527-605. Chinnery PF and Turnbull DM. (1999) Mitochondrial DNA and disease. Lancet 354 : 17–21. Chinnery PF, Samuels DC, Elson J and Turnbull DM. (2002) Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360 : 1323-1325. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L and Ueland PM (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55 : 1449-1455. Clayton DA and Vinograd J. (1967) Circular dimer and catenate forms of mitochondrial DNA in human leukaemic leucocytes. Nature 216 : 652-657. Clifford AJ, Heid MK, Muller HG and Bill ND (1990) Tissue distribution and prediction of total body folate of rats. J Nutr 120: 1633-1639. Cook RJ and Blair JA. (1979) The distribution and chemical nature of radioactive folates in rat liver cells and rat liver mitochondria. Biochem J 178 : 651-659. Corral-Debrinski M, Stepien G, Shoffner JM, Lott MT, Kanter K and Wallace DC. (1991) Hypoxemia is associated with mitochondrial DNA damage and gene induction. Implications for cardiac disease. JAMA 266 : 1812-1816. Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. (1992) Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet. 2 : 324-329. Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, McKee AC, Beal MF, Graham BH, Wallace DC. (1994) Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. Genomics. 23 : 471-476 Cortopassi GA and Wong A. (1999) Mitochondria in organismal aging and degeneration. Biochim Biophys Acta 1410 : 183-193. Cortopassi GA, Shibata D, Soong NW and Arnheim N. (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci U S A 89 : 7370-7374. Courtemanche C, Huang AC, I ES, Kerry N, Ng BY and Ames BN. (2004) Folate deficiency and ionizing radiation cause DNA breaks in primary human lymphocytes: a comparison. FASEB J 18:209-11. Craciunescu CN, Brown EC, Mar MH, Albright CD, Nadeau MR, Zeisel SH. (2004) Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain.J Nutr 134 : 162-166. Croteau DL, Stierum RH and Bohr VA. (1999) Mitochondrial DNA repair pathways. Mutat Res 434 : 137-148. Crott JW, Choi SW, Branda RF and Mason JB. (2005) Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats. Mutat Res 570 : 63-70. Davis AF, Ropp PA, Clayton DA and Copeland WC. (1996) Mitochondrial DNA polymerase gamma is expressed and translated in the absence of mitochondrial DNA maintenance and replication.Nucleic Acids Res 24 : 2753-2759. Diaz F, Bayona-Bafaluy MP, Rana M, Mora M, Hao H and Moraes CT. (2002) Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control. Nucleic Acids Res 30 : 4626-4633. Doshi SN, McDowll IFW, Moat SJ, Lang D, Newcombe RG, Kredan MB, Lewis MJ and Goodfellow J (2001) Folate improves endothelial function in coronary artery disease : an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol 21 : 1196-1202. Duan W, Ladenheim B, Cutler RG, Kruman II, Cadet JL and Mattson MP. (2002) Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease. J Neurochem. 80 : 101-110. Duthie SJ and Hawdon A. (1998) DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro. FASEB J 12 : 1491-1497. Duthie SJ, Grant G and Narayanan S. (2000) Increased uracil misincorporation in lymphocytes from folate-deficient rats. Br J Cancer 83 : 1532-1537. Edris W, Burgett B, Stine OC and Filburn CR. (1994) Detection and quantitation by competitive PCR of an age-associated increase in a 4.8-kb deletion in rat mitochondrial DNA. Mutat Res. 316 : 69-78. Eichholzer M, Luthy J, Moser U and Fowler B. (2001) Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence. Swiss Med Wkly 131 : 539-49. Fang JY, Xiao SD, Zhu SS, Yuan JM, Qiu DK and Jiang SJ. (1997) Relationship of plasma folic acid and status of DNA methylation in human gastric cancer. J Gastroenterol 32 : 171-175. Fenech M, Aitken C and Rinaldi J (1998) Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis 19 : 1163–1171. Fliss MK, Usadel H and Cabellero OL. (2000) Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287 : 2017-2019. Filser N, Margue C and Richter C. (1997) Quantification of wild-type mitochondrial DNA and its 4.8-kb deletion in rat organs. Biochem Biophys Res Commun 233 : 102-107. Fukushima S, Honda K, Awane M, Yamamoto E, Takeda R, Kaneko I, Tanaka A, Morimoto T, Tanaka K and Yamaoka Y. (1995) The frequency of 4977 base pair deletion of mitochondrial DNA in various types of liver disease and in normal liver. Hepatology 21 : 1547-1551. Gadaleta MN, Rainaldi G, Lezza AM, Milella F, Fracasso,F and Cantatore P. (1992). Mitochondrial DNA copy number and Mitochondrial DNA deletion in adult and senescent rats. Mutation Research 275 : 181-193. Garcia-Martinez LF, Appling DR. Characterization of the folate dependent mitochondrial oxidation of carbon 3 of serine. Biochemistry 1993;32:4671–6. Gregory III JF, Cuskelly GK, Shane B, Toch JP, Baumgartner TG and Stecpole P (2000) Primed, constant infusion with [2H3] serine allows in vivo kinetic measurement of serine turnover, homocysteine remethylation, and transsulfuration processes in human one-carbon metabolism. Am J Clin Nutr 72:1535-1541. Grossman LI and Shoubridge EA. (1996) Mitochondrial genetics and human disease. BioEssays 18 : 983-991. Golden TR and Melov S. (2001) Mitochondrial DNA mutations, oxidative stress, and aging. Mech Ageing Dev 122 : 1577-1589. Hayakawa M, Hattori K, Sugiyama S and Ozawa T (1992) Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts. Biochem Biophys Res Commun. 189 : 979-985. Hattori K, Tanaka M and Sugiyama S. (1991) Age-dependent increase in deleted mitochondrial DNA in the human heart: possible contributory factor to presbycardia. Am Heart J 121 : 1735-1742. Heimberger DC, Alexander CB, Birch R, Butterworth KE, Bailey WC and Krumdieck CL. (1988) Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. J Am Med Soc 259 : 1525-1530. Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers E and Shea TB. (2001) Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem 78 : 249-253. Ho PI, Dhitavat S, Ortiz D, Collins SC, Shea TB and Rogers E. (2003) Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine. Neurobiol Dis 14 : 32-42. Holt IJ, Harding AE and Morgan-Hughes JA. (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331 : 717-719. Hou JH and Wei YH. (1996) The unusual structures of the hot-regions flanking large-scale deletions in human mitochondrial DNA. Biochem J. 318 : 1065-1070. Houshmand M, Gardner A, Hallstrom T, Muntzing K, Oldfors A and Holme E. (2004) Different tissue distribution of a mitochondrial DNA duplication and the corresponding deletion in a patient with a mild mitochondrial encephalomyopathy: deletion in muscle, duplication in blood. Neuromuscul Disord 14 : 195-201. Huang RF, Ho YH, Lin HL and Wei JS, Liu TZ. (1999) Folate deficiency induces a cell cycle-specific apoptosis in HepG2 cells. J Nutr 129 : 25-31. Huang RF, Hsu YC, Lin HL and Yang FL. (2001) Folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers. J Nutr 131 : 33-8. Huang RF, Huang SM, Lin BS, Hung CY and Lu HT (2002) N-Acetylcysteine, vitamin C and vitamin E diminish homocysteine thiolactone-induced apoptosis in human promyeloid HL-60 cells. J Nutr 132 : 2151-2156. Jhaveri MS, Wangner C and Trepel JB (2001) Impact of extracellular folate level on global gene expression. Mol Pharmacol 60 : 1288-1295. Joshi R, Adhikari S, Patro BS, Chattopadhyay S and Mukherjee T (2001) Free radical scavenginf behavior of folic acid : evidence for possible antioxidant activity. Free Radic Biol Med 30 : 1390-1399. Kastanos EK,Woldman YY and Appling DR. (1997) Role of mitochondrial and cytoplasmic serine hydroxymethyltransferase isozymes in de novo purine synthesis in Saccharomyces cerevisiae. Biochemistry 36:14956–14964. Kao S, Chao HT and Wei YH. (1995) Mitochondrial deoxyribonucleic acid 4977-bp deletion is associated with diminished fertility and motility of human sperm. Biol Reprod 52 : 729-736. Kao SH, Chao HT and Wei YH. (1998) Multiple deletions of mitochondrial DNA are associated with the decline of motility and fertility of human spermatozoa. Mol Hum Reprod 4 : 657-666. Khrapko K, Coller H, Andre P, Li XC, Hanekamp JS and Thilly WG. (1997) Mitochondrial mutational spectra in human cells and tissues. Proc Natl Acad Sci USA 94 : 13798-13803. Kim YI., Pogribny IP, Basnakian AG, Miller JW, Selhub J, James SJ and Mason JB (1997) Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am. J Clin Nutr 65:46-52. King CM, Bristow-Craig HE, Gillespie ES and Barnett YA. (1997) I n vivo antioxidant status, DNA damage, mutation and DNA repair capacity in cultured lymphocytes from healthy 75- to 80-year-old humans. Mutat Res. 377 : 137-147. King MP and Attardi G. (1989) Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246 : 500-503. Kobayashi Y, Momoi MY, Tominaga K, Momoi T, Nihei K, Yanagisawa M, Kagawa Y and Ohta S. (1990) A point mutation in the mitochondrial tRNA(Leu)(UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). Biochem Biophys Res Commun 173 : 816-822. Kotake K, Nonami T, Kurokawa T, Nakao A, Murakami T and Shimomura Y. (1999) Effects of chronic liver diseases on mitochondrial DNA transcription and replication in human liver. Life Sci 65 : 557-563. Kogelnik AM, Lott MT, Brown MD, Navathe SB and Wallace DC. (1998) MITOMAP: a human mitochondrial genome database –– 1998 update. Nucleic Acid Res 26 : 112-115. Koury MJ, Horne DW, Brown ZA, Pietenpol JA, Blount BC, Ames BN, Hard R and Koury ST (1997) Apoptosis of late-stage erythroblasts in megaloblastic anemia: association with DNA damage and macrocyte production. Blood 89 : 4617-4623. Koury MJ, Price JO and Hicks GG (2000) Apoptosis in megaloblastic anemia occurs during DNA synthesis by a p53-independent, nucleoside-reversible mechanism. Blood 96 : 3249-3255. Kowaltowski AJ and Vercesi AE. (1999) Mitochondrial damage induced by conditions of oxidative stress. Free Rad Biol Med 26 : 463–471. Krahenbuhl S, Stucki J and Reichen J. (1989) Mitochondrial function in carbon tetrachloride-induced cirrhosis in the rat. Qualitative and quantitative defects. Biochem Pharmacol 38 : 1583-1588. LaBiche RA, Yoshida M, Gallick GE, Irimura T, Robberson DL, Klostergaard J and Nicolson GL. (1988) Gene expression and tumor cell escape from host effector mechanisms in murine large cell lymphoma. J Cell Biochem 36 : 393-403. LaBiche RA, Demars M and Nicolson GL. (1992) Transcripts of the mitochondrial gene ND5 are overexpressed in highly metastatic murine large cell lymphoma cells. In Vivo 6 : 317-324. Larsson NG. and Clayton DA. (1995) Molecular genetic aspects of human mitochondrial disorders. Annu Rev Genetics 29 : 151-178. Lashner BA, Provencher KS, Seidner DL, Knesebeck A and Brzezinski A (1997) The effect of folate supplementation on the risk for cancer or dysplasia in ulcerative colitis. Gastroenterology 112 : 29-32. Lee BJ, Lin PT, Liaw YP, Chang SJ, Cheng CH and Huang YC (2003) Homocysteine and risk of coronary artery disease: Folate is the important determinant of plasma homocysteine concentration. Nutrition 19 : 577-583. Lee HC and Wei YH. (2000). Mitochondrial role in life and death of the cell. J Biomed Sci. 7 : 2-15. Lenaz G. (1998) Role of mitochondria in oxidative stress and ageing. Biochim. Biophys Acta 1366 : 53-67. Lestienne P and Ponsot G. (1988) Kearns–Sayre syndrome with muscle mitochondrial deletion. Lancet 1 : 885. Lezza AM, Mecocci P, Cormio A, Beal MF, Cherubini A, Cantatore P, Senin U and Gadaleta MN. (1999) Mitochondrial DNA 4977 bp deletion and OH8dG levels correlate in the brain of aged subjects but not Alzheimer's disease patients. FASEB J. 13 : 1083-1088. Li GM, Presnell SR and Gu L (2003) Folate deficiency, mismatch repair-dependent apoptosis, and human disease. J Nutr Biochem 14 : 568-575. Linder MC ed (1985) Nutrition and metabolism of vitamins in nutritional biochemistry and metabolism with clinical applications. p89-94. Linnane AW, Baumer A, Maxwell RJ, Preston H, Zhang CF and Marzuki S. (1990) Mitochondrial gene mutation: the ageing process and degenerative diseases. Biochem Int 22 : 1067-1076. Luciakova K and Kuzela S. (1992) Increased steady-state levels of several mitochondrial and nuclear gene transcripts in rat hepatoma with a low content of mitochondria. Eur J Biochem 205 : 1187-1193. Lu CY, Lee HC, Fahn HJ and Wei YH. (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. Machlin LJ (1991) Handbook of vitamins 2nd ed. 453-490. Malaguarnera M, Ferri R, Bella R, Alagona G, Carnemolla A and Pennisi G. (2004) Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med. 42 : 1032-1035. Malinow MR, Beamer N, Sexton G, Nordt F and de Garmo P. (1990) Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke. Stroke 21 : 572-576. Marcelino LA and Thilly WG. (1999) Mitochondrial mutagenesis in human cells and tissues. Mutat Res 434 : 177-203. Martinez-Cayuela M. (1995) Oxygen free radicals and human disease. Biochimie 77 : 147-161. Maximo V, Soares P, Seruca R and Sobrinho-Simoes M. (1999) Comments on: mutations in mitochondial control region DNA in gastric tumors of Japanese patients. Eur J Cancer 35 : 1407-1408. Mayer EL, Jacobsen DW and Robinson K (1996) Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 27 : 517-527. Melnyk S, Pogribna M, Miller BJ, Basnakian AG, Pogribny IP and James SJ (1999) Uracil misincorporation, DNA strand breaks, and gene amplification are associated with tumorigenic cell transformation in folate deficient/repleted Chinese hamster ovary cells. Cancer Lett 146 : 35-44. Michaels GS, Hauswirth WW and Laipis PJ. (1982) Mitochondrial DNA copy number in bovine oocytes and somatic cells. Dev Biol 94 : 246-251. Miller, RA. (1996) The aging immune system: primer and prospectus Science 273, 70–74. Morocz M, Kalman J, Juhasz A, Sinko I, McGlynn AP, Downes CS, Janka Z and Rasko I. (2002) Elevated levels of oxidative DNA damage in lymphocytes from patients with Alzheimer's disease. Neurobiol Aging 23 : 47-53. Mohamed SA, Wesch D, Blumenthal A, Bruse P, Windler K, Ernst M, Kabelitz D, Oehmichen M and Meissner C. (2004) Detection of the 4977 bp deletion of mitochondrial DNA in different human blood cells. Exp Gerontol 39 : 181-188. Morocz M, Kalman J, Juhasz A, Sinko I, McGlynn AP, Downes CS, Janka Z and Rasko I. (2002) Elevated levels of oxidative DNA damage in lymphocytes from patients with Alzheimer's disease. Neurobiol Aging 23 : 47-53. Nakata R. (2000) Determination of folate derivatives in rat tissues during folate deficiency. J Nutr Sci Vitaminol (Tokyo). 46 : 215-221. Newman EM and Tsai JF. (1986) Microbiological analysis of 5-formyltetrahydrofolic acid and other folates using an automatic 96-well plate reader.Anal Biochem. 154 : 509-515. Noji H, Yasuda R, Yoshida M and Kinosita K Jr. (1997) Direct observation of the rotation of F1-ATPase. Nature 386 : 299-302. Ozawa T., Tanaka M., Ikebe S., Ohno K., Kondo T and Mizuno Y(1990b)Quatitive determination od deleted mitochondrial DNA relative to normal DNA in parkinosonian striatum by a kinetic PCR analysis. Biochem Biophys Res Commun 172:483-489. Ozawa T. (1997) Genetic and functional changes in mitochondria associated with aging. Physiol Rev 77 : 425-464. Pallotti F, Chen X, Bonilla E and Schon EA. (1996) Evidence that specific mtDNA point mutations may not accumulate in skeletal muscle during normal human aging. Am J Hum Genet 59 : 591-602. Penta JS., Johnson FM, Wachsman JT and Copeland WC. (2001) Mitochondrial DNA in human malignancy Mutat Res 488 : 119-133. Pogribny IP, Basnakian AG, Miller BJ, Lopatina NG, Poirier LA and James S J. (1995) Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Res 55 : 1894-1901 Poirier LA., Brown AT, Fink LM, Wise CK, Randolph CJ, Delongchamp RR and Fonseca VA. (2001) Blood S-adenosylmethionine concentrations and lymphocyte methylenetetrahydrofolate reductase activity in diabetes mellitus and diabetic nephropathy. Metabolism 50:1014 - 1018. Polyak K, LI Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW and Vogelstein B. (1998) Somatic mutations of the mitochondrial genome in human colorectal tumors. Nature Genet 20 : 291-293. Porteous WK, James AM, Sheard PW, Porteous CM, Packer MA, Hyslop SJ, Melton JV, Pang CY, Wei YH and Murphy MP. (1998) Bioenergetic consequences of accumulating the common 4977-bp mitochondrial DNA deletion. Eur J Biochem 257 : 192-201. Qureshi M, Khsandwala H, Haq IU and Prasad K. (2003) Elevated levels of plasma homocysteine in hypertensive patients with diabetes mellitus. J Cardiovasc Pharmacol Ther 8 : 261-266. Reddi AS, Jyothirmayi GN, DeAngelis B, Frank O, Baker H. (1993) Tissue concentrations of water-soluble vitamins in normal and diabetic rats. Int J Vitam Nutr Res 63 : 140-144. Richter C. (1995) Oxidative damage to mitochondrial DNA and its relationship to aging. Int J Biochem Cell Biol 27 : 647-653. Robinson CH, Lawler, MR, Chenoweth WL and Garwick AE. (1990) Normal and therapeutic nutrition. Macmillan publishing company, New York. Saraste M. Oxidative phosphorylation at the fin de siecle. (1999) Science 283 : 1488-1493 Sawyer DE and Houten BV. (1999) Repair of DNA damage in mitochondria. Mutat Res 434 : 161-176. Savre-Train I, Piatyszek MA and Shay JW. (1992) Transcription of deleted mitochondrial DNA in human colon adenocarcinoma cells. Human Mol Gene. 1 : 203-204. Scarpulla RC. (1997) Nuclear control of respiratory chain expression in mammalian cells. J Bioenerg Biomembr 29 : 109-119. Senior AE. (1988) ATP synthesis by oxidative phosphorylation. Physiol Rev 68 : 177-231. Serot JM, Christman D, Dubost T, Bene MC and Faure GC. (2001) CSF-folate levels are decreased in late-onset AD patients. J Neural Transm 108 : 93-99. Schon EA, Hirano M and DiMauro S. (1994) Mitochondrial encephalomyopathies: clinical and molecular analysis. J Bioenerg Biomembr. 26 : 291-299. Shigenaga MK, Hagen TM and Ames BN. (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91 : 10771–10778. Shoffner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan DA and Wallace DC. (1989) Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci U S A. 86 : 7952-7956. Sibani S, Melnyk S, Pogribny IP, Wang W, Hiou-Tim F, Deng L, Trasler J, James SJ and Rozen R. (2002) Studies of methionine cycle intermediates (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in Min mice. Carcinogenesis. 23 : 61-5. Simonetti S, Chen X, DiMauro S and Schon EA. (1992) Accumulation of deletions in human mitochondrial DNA during normal aging: analysis by quantitative PCR. Biochim Biophys Acta 1180 : 113-122. Singh G, Sharkey SM and Moorehead R. (1992) Mitochondrial DNA damage by anticancer agents. Pharmac Ther 54 : 217-230. Skehel JM, Fearnley IM and Walker JE. (1998) NADH:ubiquinone oxidoreductase from bovine heart mitochondria: sequence of a novel 17.2-kDa subunit. FEBS Lett 438 : 301-305. Smith, O.P., Hann, I.M., Woodward, C.E. & Brockington, M. (1995) Pearson’s marrow/pancreas syndrome: haematological features associated with deletion and duplication of mitochondrial DNA. Br. J. Haematol. 90: 469-472. Snowdon DA, Tully CL, Smith CD, Riley D and Markesbery W. (2000) Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun Study. Am J Clin Nutr 71 : 993-998. Sohn KJ , Stempak JM, Reid S , Shirwadkar S, Mason JB and Kim YI (2003) The effect of dietary folate on genomic and p53-specific DNA methylation in rat colon. Carcinogenesis 24 : 81-90. Sohal RS, Agarwal S, Dubey A and Orr WC. (1993) Protein oxidative damage is associated with life expectancy of houseflies. Proc Natl Acad Sci U S A. 90 : 7255-7259. Stabler SP, Estacio R, Jeffers BW, Cohen JA, Allen RH and Schrier RW. (1999) Total homocysteine is associated with nephropathy in non-insulin-dependent diabetes mellitus. Metabolism 48 : 1096-101. Sugiyama S, Takasawa M, Hayakawa M and Ozawa T. (1993) Changes in skeletal muscle, heart and liver mitochondrial electron transport activities in rats and dogs of several ages. Biochem Mol Biol Int 30 : 937-944. Suliman HB, Carraway MS, Welty-Wolf KE, Whorton AR and Piantadosi CA. (2003). Lipopolysaccharide stimulatesmitochondrial biogenesis via activation of nuclear respiratory factor-1. J Biol Chem 278 : 41510-41518. Suzuki S, Hinokio Y, Komatu K, Ohtomo M, Onoda M, Hirai S, Hirai M, Hirai A, Chiba M, Kasuga S, Akai H and Toyota T.(1999)Oxidative damage to mitochondrial DNA and its relationship to diabetic complications. Diabet Res Clin Pract 45:161-168. Taanman JW. (1999) The mitochondrial genome : structure, transcription, translation and replication. Biochim Biophys Acta 1410 : 103-123 Tarng DC, Wen Chen T, Huang TP, Chen CL, Liu TY and Wei YH. (2002) Increased oxidative damage to peripheral blood leukocyte DNA in chronic peritoneal dialysis patients. J Am Soc Nephrol. 13 : 1321-1330. Tamura G, Nishizuka S, Maesawa C, Suzuki Y, Iwaya T, Sakata K, Endoh Y and Motoyama T. (1999) Mutations in mitochondrial control region DNA in gastric tumors of Japanese patients, Eur J Cancer 35 : 316-319. Thompson JR, Gerald PF, Willoughby ML and Armstrong BK. (2001) Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control study. Lancet 358 : 1935-1940. Title LM, Cummings PM, Giddens K, Genest JJJ and Nassar BA. (2000) Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 36:758-65. Tough DF and Sprent J. (1995) Lifespan of lymphocytes. Immunol Res 14 : 1-12. Toyokuni S, Okamoto K, Yodoi J and Hiai H. (1995) Persistent oxidative stress in cancer. FEBS Lett 358 : 1-3. Trounce IA, Kim YL, Jun AS and Wallace DC. (1996) Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines. Methods Enzymol 264 : 484-509. Upchurch GRJ, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF J and Loscalzo J. (1997) Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem. 272: 17012-17017. Vecchia LC, Negri E, D'Avanzo B, Boyle P and Franceschi S. (1990) Medical history and primary liver cancer. Cancer Res 50 : 6274-6277. Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH, Stabler SP, Reynolds RD, Kok FJ, Hennekens CH and Willett WC. (1996) Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol 143 : 845-859. Virbasius JV, Virbasius CA and Scarpulla RC. (1993a) Identity of GABP with NRF-2, a multisubunit activator of cytochrome oxidase expression, reveals a cellular role for an ETS domain activator of viral promoters. Genes Dev 7 : 380-392. Virbasius CA, Virbasius JV and Scarpulla RC. (1993b) NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators. Genes Dev 7 : 2431-2445. Virbasius CA, Virbasius JV and Scarpulla RC. (1993) NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators. Genes Dev. 7 : 2431-2345. Virbasius JV and Scarpulla RC. (1994) Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci U S A 91 : 1309-1313. Wainfan E and Poirier LA. (1992) Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. Cancer Res. 52 : 2071s-2077s. Wald NJ, Law MR, Morris JK and D Wald S. (2001) Quantifying the effect of folic acid. Lancet 358 : 2069-2073. Wallace DC. (1997) Mitochondrial DNA in aging and disease. Scientific Am 277 : 40-47. Wallace DC, Ye J, Necklemann SN, Singh G, Webster KA and Greenberg BD. (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. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ and Nikoskelainen EK. (1988) Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242 : 1427-1430. Wallace DC, Zheng XX, Lott MT, Shoffner JM, Hodge JA, Kelley RI, Epstein CM and Hopkins LC. (1988) Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell 55 : 601-610. Wang H, Fliegel L, Cass CE, Penn AM, Michalak M, Weiner JH and Lemire BD. (1994) Quantification of mitochondrial DNA in heteroplasmic fibroblasts with competitive PCR. Biotechniques 17 : 76 - 78, 80, 82. Wang HX, Wahlin A, Basun H, Fastom J, Winblad B and Fratiglioni L. (2001) Vitamin B12 and folate in relation to the development of Alzheimer's disease. Neurology 56 : 1188-1194. Welch GN and Loscalzo J (1998) Homocystine and atherotherombosis. New Engl J Med 338 : 1042-1050. Wei YH, Scholes CP and King TE. (1981) Ubisemiquinone radicals from the cytochrome b-c1 complex of mitochondrial electron transport chain: emonstration of QP-S radical formation. Biochem Biophys Res Commun 99 : 1411-1419. Wei YH. (1992) Mitochondrial DNA alterations as ageing-associated molecular events. Mutat Res 275, pp. 145-155. Wei YH. (1998a) Oxidative stress and mitochondrial DNA mutations in human aging. Proc Soc Exp Biol Med 217 : 53-63. Wei YH, Lu CY, Lee HC, Pang CY and Ma YS. (1998b) Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function. Ann N Y Acad Sci 854 : 155-170. Wei YH and Lee HC. (2002) Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med 227:671-682. Wu A, Chanarin I, Slavin G and Levi AJ. (1975) Folate deficiency in the alcoholic--its relationship to clinical and haematological abnormalities, liver disease and folate stores.Br J Haematol 29 : 469-478. Wurmb VN, Oehmichen, M. & Meissner, C. (1998) Demonstration of the 4977 bp deletion in human mitochondrial DNA from intravital and postmortem blood. Mutat. Res. 422: 247-254. Yamamoto H, Tanaka M, Katayama M, Obayashi T, Nimura Y and Ozawa T. (1992) Significant existence of deleted mitochondrial DNA in cirrhotic liver surrounding hepatic tumor. Biochem Biophys Res Commun 182 : 913-920. Yen TC, Su JH, King KL and Wei YH. (1991) Ageing-associated 5 kb deletion in human liver mitochondrial DNA. Biochem Biophys Res Commun 178 : 124-131. Yakes FM and Van Houten B. (1997) Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci U S A 94 : 514-549. Zhang J, Montine TJ, Smith MA, Siedlak SL, Gu G, Robertson D and Perry G. (2002) The mitochondrial common deletion in Parkinson's disease and related movement disorders. Parkinsonism Relat Disord 8 : 165-170.
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