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研究生:葉宜玲
研究生(外文):Ye iling
論文名稱:粒線體葉酸代謝之抗氧化壓力對保護粒線體DNA、粒線體增生與功能性之影響
論文名稱(外文):The role of mitochondrial folate metabolism to protect against oxidant stress-induced mitochondrial DNA injuries, enhanced mitochondrial biogenesis and mitochondrial dysfunction
指導教授:許瑞芬許瑞芬引用關係
指導教授(外文):Rwei-Fen S. Huang
學位類別:碩士
校院名稱:輔仁大學
系所名稱:營養科學系
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:185
中文關鍵詞:粒線體葉酸粒線體生合成8-OHdGmtDNA大片斷斷損中國大頰鼠卵巢細胞
外文關鍵詞:mitochondrial folatemitochondrial biogenesis8-OHdGΔmtDNA4.8CHO cell
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氧化壓力的增加會誘發粒線體增生及功能損性傷。葉酸為一抗氧化營養分子,但粒線體葉酸擔任保護粒線體的角色尚未被了解。本研究選用中國大頰鼠卵巢細胞粒線體葉酸代謝正常野生株CHOK1,與粒線體serine hydroxylmethyltransferase酵素 (mSHMT) 缺陷突變株GLYA及粒線體葉酸轉運蛋白缺陷突變株GLYB為研究模式。探討粒線體葉酸代謝如何保護粒線體功能、DNA與調節粒線體生合成機制。投與外來氧化壓力t-butylhyhroperoxide (t-BH) 處理24、48 與72小時後,以細胞流式儀偵測胞內活性氧物種含量、粒線體質量與粒線體膜電位變化;即時定量PCR測定調節粒線體生合之轉錄因子表現、粒線體DNA (mtDNA) 拷貝數與4834bp大片斷損量 (ΔmtDNA4.8 kb);並以HPLC測量DNA氧化傷害指標8-Hydroxydeoxyguanosine (8-OHdG) 含量;以微生物法分析葉酸含量。結果顯示,GLYB突變株細胞質與粒線體葉酸含量顯著低於CHOK1。胞內超氧陰離子含量顯著高於CHOK1與GLYA。t-BH處理後,顯著消耗細胞質與粒線體葉酸含量分別下降44%與28%,且胞內過氧化氫與超氧陰離子顯著增加4倍。t-BH處理24小時後,GLYB之粒線體生合成相關轉錄因子NRF-1、NRF-2、mtTFA與mtDNA複製因子pol γ皆向上調節,啟動粒線體生合成提早,並伴隨mtDNA拷貝數與粒線體質量增加。ROS大量產生,促使GLYB細胞內DNA氧化損傷8-OHdG增加3倍,mtDNA 4834 bp大片段斷損 (ΔmtDNA4.8 kb) 顯著累積,mtDNA轉譯之COX I、II及III基因發生點突變機率增加,導致粒線體膜電位去極化比例增加1.7倍。GLYA突變株,在t-BH處理後,顯著消耗細胞質與粒線體葉酸含量 (22%與48%),且胞內ROS增加3倍,促使粒線體生合成相關轉錄因子NRF-1、mtTFA向上調節,並伴隨mtDNA拷貝數與粒線體質量增加,但其粒線體生合成比GLYB晚被啟動。ROS的產生,促使GLYA細胞內8-OHdG含量增加2倍,ΔmtDNA4.8 kb累積,導致粒線體膜電位去極化比例增加,但其氧化傷害介於CHOK1與GLYB之間。葉酸補充可顯著增加GLYA與GLYB細胞質與粒線體中葉酸濃度,並降低細胞因外因性氧化壓力誘發大量ROS產生,顯著降低胞內8-OHdG含量、ΔmtDNA4.8kb累積與點突變之發生,達到保護mtDNA之功能,恢復粒線體膜電位。並調節ROS誘發粒線體生合成相關轉錄因子表現,mtDNA拷貝數與粒線體質量隨之降低。縱合上述,粒線體葉酸具有保護粒線體DNA抗氧化傷害及維持粒線體膜電位正常功能。並平衡外來氧化壓力、調整細胞核啟動粒線體增生機制,以補償氧化壓力對粒線體傷害。補充葉酸可改善粒線體葉酸代謝酵素基因變異或生化缺陷,以補足粒線體葉酸不足,降低外因性氧化壓力誘發之氧化傷害。
Increased oxidative stress results in mitochondrial (mt) DNA damage, mt dysfunction and enhanced mt biogenesis. The aims of the study is to investigable the mt folate metabolism to protect against oxidant stress-induced mtDNA injuries, enhanced mt biogenesis and mt dysfunction. Several Chinese hamster ovary (CHO) cells including wild type CHOK1 with normal mt folate metabolism, GLYA mutants with defective mt serine hydroxyl- methyltransferase defective, and GLYB mutant with defective mt folate transport protein defective were used as experimental models to explore molecular mechanisms by which mt folate may have impact on mt biogenesis and function. CHO cells were treated with t-butylhyhroperoxide (t-BH) for 24, 48, and 72 hr. Intracellular reactive oxygen species, mt mass and mt membrane potential were measured by flow cytometry. Gene expressions of transcription factors for mt biogenesis, mt DNA (mtDNA) copy numbers and 4834bp large deletion (ΔmtDNA4.8) of mtDNA were assayed by real-time polymerase chain reaction. Levels of 8-hydroxydeoxyguanosine (8-OHdG) were measured by HPLC complete with ECD. Folate levels were measured by L. cassia method. Cytosolic and mt folate of GLYB was significantly lower than those of CHOK1. Intracellular superoxide of GLYB was significantiy higher than those of CHOK1 and GLYA. After t-BH treatment, the cytosolic and mt folate levels of GLYB decreased by 44 and 28%, respectively. ROS in GLYB increases by 4 fold of it’s untreated-values. This markedly elevated oxidative stress in GLYB appeared to induce expressions of transcription factors for mt biogenesis including NRF-1, NRF-2, mtTFA and Pol γ at 24 hr-treat of t-BH, which accompanied increased mtDNA copy numbers and mt mass. In parallel, t-BH treatment for 24hr induced higher levels of 8-OHdG and ΔmtDNA4.8 accumulated in GLYB compared to those in CHOK1. Frequencies of point mutations in mtDNA encoded for COX I, II and III subunits of cytochrome c oxidase were increased. Ratio of t-BH-treated GLYB with depolarized mt membrane potential was increased by 1.7 fold. T-BH-treated GLYA showed the intermediate responses of mtDNA injuries, mt biogenesis and mt dysfunction compared to those of t-BH treated GLYB. Pre-incubation of mutants cells with folate supplements significant increase both cytosolic and mt folate, and reduced the t-BH-induced ROS. Folate supplementation could reduce in t-BH treated GLYA and GLYB levels of 8-OHdG, ΔmtDNA4.8 accumulateion and point mutation frequencies. The expressions of transcription factors for mt biogenesis by ROS induced were partially modulated by folate supplement, which accompanied reduced mtDNA copy number and mt mass. In summary, the mt folate had antioxidant capability to protect against oxidative stress-induced ROS generation, mtDNA damage, and mt membrane potential depolaritation, and enhanced mt biogenesis. Folate supplementation could offset mt deficiency as the result of defective mt folate metabolism and protect against t-BH-induced mtDNA damage and dysfunction.
目錄

中文摘要............................................................I
英文摘要..........................................................III
縮寫表..............................................................V
圖目錄............................................................XIV
表目錄............................................................XIX
第一章 前言..........................................................1
第二章 文獻回顧.......................................................2
一、氧化壓力對粒線體之影響...........................................2
(一) 粒線體為內生性氧化壓力來源.....................................2
(二) 氧化壓力對粒線體之傷害........................................3
1. 氧化壓力與呼吸酵素複體IV ...................................4
2. 氧化壓力與粒線體DNA突變.....................................7
(1) 大片段斷損的產生..........................................7
(2) 8-hydroxy 2’-deoxyguanosine的產生........................8
(3) 點突變的產生..............................................10
3. 氧化壓力與粒線體膜電位......................................10
(三) 氧化壓力啟動粒線體之生合成機制...............................11
二、葉酸.........................................................15
(一)、葉酸之生化代謝............................................15
(二)、葉酸主導細胞質與粒線體之單碳代謝............................16
(三)、葉酸缺乏誘發氧化壓力產生....................................17
(四)、葉酸缺乏對粒線體之影響.....................................19
(五)、粒線體葉酸代謝異常對細胞變異之影響...........................20
1. GLYA......................................................21
2. GLYB...............................................................22
三、研究目的.................................................................24
第三章 實驗材料與方法................................................25
一、實驗材料......................................................25
(一)、細胞株.................................................25
(二)、培養基與儀器設備.........................................25
二、實驗方法......................................................26
(一)、細胞陪養.................................................26
(二)、氧化劑配製...............................................26
(三)、細胞內ROS含量之測定......................................26
(四)、細胞粒線體膜電位之測定....................................28
(五)、細胞粒線體膜質量測定......................................28
(六)、DNA氧化傷害測定..........................................29
(七)、粒線體DNA之分析..........................................31
(八)、Reverse transcription-polymerase chain reaction (RT-PCR).....36
(九) 即時定量聚合酶連鎖反應 (real-time PCR)....................39
(十) 葉酸含量分析............................................44
(十一) 統計分析..............................................46
第四章 結果 I .....................................................47
氧化壓力敏感之粒線體葉酸代謝異常細胞株誘發粒線體葉酸缺乏、粒線體DNA損傷、粒線體生合成與功能性損傷
ㄧ、t-BH處理對CHOK1,GLYA與GLYB之細胞內葉酸濃度之影響....................................................................................................47
二、不同時間點t-BH誘發CHOK1、GLYA與GLYB細胞內過氧化氫與超氧陰離子含量之影響........................................................47
三、不同時間點t-BH處理對CHOK1、GLYA及GLYB之粒線體生合成轉錄因子之調節....................................................................49
四、不同時間點t-BH處理對CHOK1、GLYA及GLYB之粒線體增生之影響........................................................................................51
五、不同時間點t-BH處理對CHOK1、GLYA及GLYB之mtDNA大片段斷損之影響........................................................................53
六、t-BH處理對粒線體葉酸缺乏之GLYB細胞粒線體COX I部分基因突變性之影響........................................................................54
七、t-BH處理對粒線體葉酸缺乏之GLYB細胞粒線體COX II部分基因突變性之影響........................................................................55
八、t-BH處理對粒線體葉酸缺乏之GLYB細胞粒線體COX III部分基因突變性之影響....................................................................56
九、不同時間點t-BH處理對CHOK1、GLYA及GLYB之細胞核DNA轉錄之粒線體呼吸鏈酵素基因mRNA表現量之影響....56
十、不同時間點t-BH處理對CHOK1、GLYA及GLYB之粒線體COX次單元及部份粒線體基因轉錄mRNA表現量之影響....57
第五章 結果 II.......................................................................................59
補充葉酸對外因性氧化壓力誘發粒線體葉酸代謝異常細胞株粒線體氧化傷害之調節
ㄧ、葉酸補充與t-BH處理對CHOK1、GLYA及GLYB之細胞質與粒線體葉酸濃度之調節.............................................................59
二、葉酸補充與t-BH處理誘發CHOK1、GLYA及GLYB細胞內過氧化氫含量之影響.....................................................................60
三、葉酸補充與t-BH處理對CHOK1、GLYA及GLYB細胞內超氧陰離子含量之影響.....................................................................60
四、葉酸補充與t-BH處理對CHOK1、GLYA及GLYB之DNA氧化傷害指標8-OHdG含量之影響..............................................61
五、葉酸補充與t-BH處理對CHOK1、GLYA及GLYB之mtDNA大片段斷損之影響.....................................................................62
六、葉酸補充與t-BH處理對粒線體葉酸缺乏之GLYB細胞粒線體COX I部分基因突變性之影響..................................................63
七、葉酸補充與t-BH處理對粒線體葉酸缺乏之GLYB細胞粒線體COX II部分基因突變性之影響.................................................63
八、葉酸補充與t-BH處理對粒線體葉酸缺乏之GLYB細胞粒線體COX III部分基因突變性之影響...............................................64
九、葉酸補充與t-BH處理對CHOK1、GLYA及GLYB之mtDNA及細胞核DNA轉譯之次單元mRNA表現量之影響...............65
十、葉酸補充與t-BH處理對CHOK1、GLYA及GLYB之粒線體膜電位之影響.................................................................................68
十ㄧ、葉酸補充與其他抗氧化劑對t-BH處理之CHOK1、GLYA及GLYB之DNA氧化傷害指標8-OHdG含量之影響.............69
十二、葉酸補充與其他抗氧化劑對t-BH處理之CHOK1、GLYA及GLYB之粒線體功能性之影響..................................................70
第六章 結果 III......................................................................................72
葉酸之補充對外因性氧化壓力誘發粒線體生合成之影響
ㄧ、葉酸補充與t-BH處理對CHOK1、GLYA及GLYB細胞內粒線體生合成轉錄因子之調節............................................................72
二、葉酸補充與t-BH處理對CHOK1、GLYA及GLYB細胞粒線體增生之影響....................................................................................76
第七章 討論............................................................................................79
第八章 結論..........................................................95
第九章 總結..........................................................97
第十章 參考文獻.....................................................147
附錄...............................................................160
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