臺灣博碩士論文加值系統

在人類老化組織及粒線體疾病患者的病變組織中，細胞呼吸功能下降並伴隨活性氧分子不斷的經由電子傳遞鏈產生，部份的活性氧分子逃避抗氧化系統的清除，進而傷害細胞及粒線體內的生化分子，可能是導致人類老化及粒線體疾病病情隨年齡增加而惡化的原因之一。
因此，在第一部份的研究中，我共收集了76個不同年齡正常人的皮膚組織，來研究氧化性損傷和自由基清除酵素與年齡的相關性。結果顯示小於60歲的個體間其8-OHdG和4,977 bp mtDNA斷損突變的含量並沒有顯著的差異，但超過60歲的個體間其8-OHdG和4,977 bp mtDNA斷損突變的含量隨著年齡增加而有顯著的增加。同樣的，皮膚纖維母細胞脂質過氧化物的含量，在大於60歲的個體也隨年齡增加而增加。為了評估不同年齡的個體皮膚纖維母細胞清除活性氧分子的能力，我測定銅鋅型超氧化物歧化(Cu,Zn-SOD)、錳型超氧化物歧化(Mn-SOD)、CAT 和穀胱甘過氧化(GPx)的活性。結果顯示Cu,Zn-SOD、CAT和GPx 的酵素活性分別隨著年齡的增加而降低，而Mn-SOD的酵素活性在超過60歲以後也逐漸降低。我進一步分析這些自由基清除酵素彼此之間在細胞內的功能是否協調，發現Cu,Zn-SOD/CAT和Cu,Zn-SOD/GPx的活性比值隨著年齡增加而減少，Mn-SOD/CAT和Mn-SOD/GPx的活性比值也在超過60歲後的個體間與年齡呈負相關。結果顯示8-OHdG及mtDNA斷損突變含量高的皮膚纖維母細胞之自由基清除酵素活性有不平衡的現象。因此，我相信自由基清除酵素之間的不平衡與氧化性損傷可能是導致老化的一個重要因子。
另一方面，我也探討這些老化個體細胞內存在的mtDNA斷損突變，是否會影響到基因轉錄及轉譯。因此我運用北方墨漬雜交法，分析不同年齡層個體之皮膚纖維母細胞mtRNA的表現量，結果並沒有顯著的差異。接著我分析不同年齡層個體之皮膚纖維母細胞粒線體呼吸酵素NCCR、SCCR和CCO的活性，發現三組不同年齡層的個體其三種酵素活性隨年齡增加而降低。值得一提的，我發現一位未罹患粒線體疾病，其皮膚纖維母細胞卻含有60% 的4,977 bp之mtDNA斷損突變的75歲老婦人，mtDNA的斷損影響RNA及呼吸酵素活性表現。可見細胞因著mtDNA斷損突變，進而調節轉錄和轉譯的機轉，以彌補能量供應的不足，但卻引發更多的電子漏，造成更多的氧化性傷害，形成一惡性循環，終於導致細胞的各種生理機能下降。
在第二部份的研究中，我收集了9位CPEO 病人來研究粒線體疾病和粒線體功能缺陷與粒線體產生過量活性氧分子的關係。因此，我針對CPEO病人的皮膚和肌纖維母細胞的mtDNA突變和氧化性損傷進行分析，我以南方墨漬法(Southern blot)分析皮膚和肌肉纖維母細胞的DNA，發現這9位病人所含的mtDNA突變差異性極大，有4,977 bp、 4,366 bp、 6,190 bp、約10 kb的大片段mtDNA斷損突變(deletion)和粒線體tRNALeu(UUR)基因的A3243G點突變。為了解mtDNA突變伴隨自由基清除酵素活性的失調是否是引發CPEO病人肌肉病變的主因。接著，我分析9位CPEO病人的皮膚和肌肉纖維母細胞的Mn-SOD、CAT和GPx酵素活性。結果顯示這9位病人的皮膚或肌纖維母細胞Mn-SOD酵素活性或mRNA量的表現量均高於控制組。相反地，CAT和GPx活性和mRNA的表現量不但沒有增加，且肌肉纖維母細胞的CAT酵素活性和mRNA的表現量較皮膚纖維母細胞低了2倍。肌肉纖維母細胞Mn-SOD/CAT的活性比值(界於3.39和8.36之間)高出控制組1.4至3.5倍。這種組織特異性的失調也同樣發生在mRNA的基因表現上;以Mn-SOD/CAT的mRNA比值而言，CPEO病人的皮膚纖維母細胞較控制組高出3倍，而肌肉纖維母細胞則高出3-8倍。同時，CPEO病人的皮膚纖維母細胞之Mn-SOD/GPx mRNA比值比正常人的細胞高出2-3倍，而肌肉纖維母細胞則高出3-4倍。很明顯地，這種產生和清除H2O2功能的失調在肌肉纖維母細胞較為嚴重。另一方面，我發現皮膚纖維母細胞之‧O2─和H2O2的含量與控制組相當或低於控制組;但是，肌肉纖維母細胞內的‧O2─和H2O2含量均高於控制組。再者，其中3位CPEO病人肌肉組織DNA中8-OHdG的含量較正常人高出6-13倍，顯示CPEO病人肌肉組織遭受較為嚴重的氧化性傷害。
綜合以上的研究，我發現不論是老化的皮膚纖維母細胞或是CPEO病人的皮膚和肌肉纖維母細胞，其自由基清除酵素的活性及基因表現量有不平衡的現象。這種不平衡誘發細胞內的氧化壓迫，進而導致DNA損傷產物8-OHdG和脂質過氧化物的累積。這些實驗結果提供了新穎而有力的証據，以解釋人類老化和CPEO粒線體疾病的致病分子機轉及自由基在這些粒線體功能異常的病變過程所扮演的角色。

The cellular respiratory functions decline in aging human tissues and affected tissues of patients with mitochondrial diseases. This is accompanied by an increase of reactive oxygen species (ROS) production in mitochondria via the increased electron leak of the respiratory chain. As a result, an ever-increasing amount of ROS may escape from the defense systems and cause oxidative damage to biomolecules.
To investigate the relationship between free radical scavenging enzymes and oxidative damage, a total of 76 normal subjects of different ages were recruited in this study. I found an age-dependent increase of 8-OHdG content and proportion of 4,977 bp mitochondrial DNA (mtDNA) deletion in skin tissues from subjects above the age of sixty years. Moreover, I also found an age-dependent increase of lipid peroxides in cultured fibroblasts of the subjects above the age of sixty years. To evaluate the antioxidant defense system from individuals of different ages, I measured the activities of Cu,Zn-superoxide dismutase (Cu,Zn-SOD), Mn-superoxide dismutase (Mn-SOD), catalase (CAT) and glutathione peroxidase (GPx). The activities of Cu,Zn-SOD, CAT and GPx were found to decrease with age, and the activity of Mn-SOD was increased with age before sixty years but was decreased thereafter. This indicated that elevated oxidative stress caused by an imbalance between the production and removal of ROS occurred in skin fibroblasts after sixty years of age. Taken together, I suggest that the functional decline of free radical scavenging enzymes and the elevation of oxidative stress may play an important role in eliciting oxidative damage and mutation of mtDNA during the human aging process.
On the other hand, I investigated the alterations of age-dependent mitochondrial gene expression associated with mtDNA deletions. Total RNAs were isolated and analyzed by Northern hybridization. There were no significant differences of the mtRNAs among the skin fibroblasts from subjects of different ages. Moreover, I measured the activities of respiratory enzymes NCCR, SCCR and CCO in fibroblasts of subjects of different ages. There was an age-dependent decrease in the activities of the three enzyme complexes. More interestingly, I found a 75-year-old woman who had no mitochondrial disease but harbored 60% of the 4,977 bp deleted mtDNA in the fibroblasts established from her face skin. This deletion caused dramatic alteration in the mRNA levels and the activities of respiratory enzymes of mitochondria.
In the second part of this study, skin and muscle fibroblasts were cultured from nine patients with chronic progressive external ophthalmoplegia (CPEO) syndrome for studying the relationship between mtDNA mutation and free radical scavenging enzymes. The skin and muscle fibroblasts from these CPEO patients carried different mtDNA mutations at different levels. The fibroblasts from patients had the common 4,977 bp mtDNA deletion, a 4,366 bp mtDNA, a 6,190 bp mtDNA deletion, a ~10 kb mtDNA deletion and the A3243G mutation in mitochondrial tRNALeu(UUR) gene. To examine whether these mtDNA mutations are associated with a defect or imbalance in the free radical scavenging enzymes. I assayed the enzyme activities of Mn-SOD, catalase and GPx of the fibroblasts. I found that the skin and muscle fibroblasts from the nine CPEO patients all had higher enzyme activity and mRNA level of Mn-SOD but those of catalase and GPx were not increased or even decreased. These results indicated an imbalance between the H2O2 generation and removal systems in the fibroblasts of the patients with CPEO syndrome. The ratios of activities of Mn-SOD/catalase in muscle fibroblasts (between 3.39 and 8.36) were about 1.4 to 3.5 fold higher than those of the control subjects. The ratios in skin fibroblasts of patients CPEO4, CPEO6, and CPEO8 were also significantly different from those of the control subjects. But the imbalance was much more pronounced in muscle fibroblasts. This tissue-specific imbalance of free radical scavengers was confirmed by analysis of the corresponding mRNA levels. The average mRNA ratio of Mn-SOD/catalase in fibroblasts of the nine CPEO patients was about 1.21 and that was 0.44 for control skin fibroblasts. By contrast, the average Mn-SOD/catalase mRNA ratio was 1.58-6.29 in muscle fibroblasts of these patients, which was much higher than those of the control fibroblasts (0.79). These results are consistent with the clinical observation that muscle is the main affected tissue of patients with CPEO syndrome. I suggest that the imbalance between free radical scavenging enzymes play an important role in the pathogenesis and age-dependent progression of the CPEO syndrome.

封面
目錄
中文摘要
英文摘要
縮寫表
第一章 緒論
1.1 活性氧和自由基
1.2 抗氧化系統如自由基清除機轉
1.3 自由基、氧化性破壞與老化
1.4 自由基老化理論的主角一粒線體
1.5 人類老化與粒線體DNA突變的關係
1.6 粒線體DNA突變和粒線體疾病的關係
1.7 表與圖
第二章 人類皮膚組織粒線體DNA突變以及人類皮膚纖維母細胞之自由基清除酵素缺陷所引發的氧化性傷害與年齡關係之研究
2.1 研究背景
2.2 研究材料與方法
2.3 結果
2.4 討論
2.5 表與圖
第三章 患有慢性進行性外眼肌病變症候群病人的皮膚和肌肉纖維母細胞自由基清除酵素缺陷所引發的氧化性壓迫與粒線體DNA突變
3.1 研究背景
3.2 研究材料與方法
3.3 結果
3.4 討論
3.5 表與圖
第四章 總結
參考文獻
個人著作目錄

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個人著作目錄
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8. Lee, H. C., Lu, C. Y., Fann, 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.
9. Wei, Y. H., Lu, C. Y., Lee, H. C., Pang, C. Y. and Ma, Y. H. (1998) Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function. Ann. N. Y. Acad. Sci. 854,155-170
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