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題 名 | Mitochondrial DNA Mutations and Oxidative Damage in Aging and Diseases: An Emerging Paradigm of Gerontology and Medicine=與人類老化和疾病有關的粒線體DNA突變及氧化性損傷--醫學和老年學正在開展中的新研究領域 |
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作 者 | 魏耀揮; | 書刊名 | Proceedings of the National Science Council : Part B, Life Science |
卷 期 | 22:2 1998.04[民87.04] |
頁 次 | 頁55-67 |
分類號 | 364.6 |
關鍵詞 | 人類粒線體DNA; 老年生物醫學; 粒線體醫學; Aging; Myopathy; Encephalomyopathy; Mitochondrial DNA; Mutation; Depletion; |
語 文 | 英文(English) |
中文摘要 | 人類粒線體DNA(mtDNA)是存在染色體外的多拷貝遺傳物質。它暴露在粒線體呼吸 鏈所產生的高濃度活性氧分子和自由基中;因而比核DNA更容易遭受氧化性破壞。過去十年 來,在老人的身體組織中已發現在二十餘種的mtDNA突變。其中4,977bp及7,436bp大幅斷 損突變和A3243G及A8344G點突變經常發生並累積在老人的肌肉及其他組織中。這些mtDNA 突變以相當低(<5%)的量單獨或同時存在於老的人類組織。再者,在人類組織中的mtDNA之 氧化性損傷也隨著年紀而增加。另一方面,已有一百餘種的mtDNA突變被發現存在一些罹患 粒線體肌肉病變及腦神經肌肉病變的病人組織中。突變型mtDNA通常與野生型mtDNA同時存 在病變組織中,這種現象稱為遺傳的異質性(heteroplasmy)。一般而言,這種疾病的臨床病 癥之嚴重程度與病變組織中之突變型mtDNA的含量(通常高於80%)有密切的相關。每一種 mtDNA突變達到可致病的最低含量都不一樣。在相同的突變比例下,mtDNA的大幅斷損突變 所造成的病癥比點突變mtDNA所引起者更為嚴重。突變型mtDNA在病人組織中的分佈及該組 織的能量需求量是該mtDNA突變的致病性之重要決定因子。突變型mtDNA通常廣泛地分佈於 病人各種組織中,因而常造成粒線體疾病患者表現多系統性功能異常。雖然大部份的致病點 突變為母系遺傳,絕大多數的大幅斷損mtDNA突變為後天偶發的。此外,mtDNA的序列重複 突變及拷貝數的減低也被發現存在一些粒線體功能異常之病患的肌肉及其他病變組織中。再 者,我們的研究室最近發現病變組織中的DNA氧化性損傷很顯著地比正常組織中的要高。這 十年來的研究已經確定mtDNA的氧化性損傷及突變為人類老化的一重要因子,而且在高量的 mtDNA突變和氧化性損傷下粒線體疾病患者的病變組織中之ATP合成與供應遠低於其能量需 求的閥值。以上這些進展已為老年生物醫學及粒線體醫學的未來發展奠定了良好的基礎。 |
英文摘要 | Human mitochondrial DNA (mtDNA) is a multi-copy extra-chromosomal genetic element, which is exposed to a high steady-state level of reactive oxygen species and free radicals generated by the respiratory chain in mitochondria. Thus, it is much more vulnerable to oxidative damage and mutation than is nuclear DNA. In the past decade, more than two-dozen mutations of mtDNA have been observed in the somatic tissues of aged individuals. Among them, the 4,977 bp and 7,436 bp deletions and the A3243G and A8344G point mutations frequently occur and accumulate exponentially with age in muscle and other human tissues. These mtDNA mutations occur alone or co-exist in old human tissues at relatively low levels (< 5%). Aside from mutation, oxidative damage to mtDNA also increases in an age-dependent manner in human tissues. On the other hand, more than a hundred mtDNA mutations have been detected in patients with mitochondrial myopathy and encephalomyopathy. The mutant mtDNA often coexists with the wild-type mtDNA in affected tissues (a condition termed heteroplasmy). Usually the clinical severity of the disease is correlated with the proportion of the mutated mtDNA in the target tissues (usually > 80%). The threshold of the mutant mtDNA which is required to elicit clinical symptoms varies with different mutations. At the same level, large-scale deletions usually cause much more severe pathologies than do point mutations. The pattern of distribution of the mutant mtDNA and the energy demand of the target tissues are important factors in determining the pathological outcome of the mutation. The mutant mtDNA is usually widely distributed in the body tissues of the patient, thereby leading to multi-system disorders, which are frequently seen in mitochondrial diseases. Although a majority of the pathogenic point mutations are maternally transmitted, large-scale deletions of mtDNA are mostly sporadic. In addition, tandem duplication and depletion of mtDNA have also been found in the muscle and other affected tissues of elderly subjects and some patients with mitochondrial myopathy. Moreover, recent work in our laboratory has shown that oxidative damage to DNA in affected tissues is significantly higher than that in normal tissues. It is now established that mutation and oxidative damage of mtDNA are contributory factors to aging and that at high levels, they cause a fall of ATP supply below the threshold of energy needed by affected tissues in patients with mitochondrial diseases. These advances have laid the foundation for the development of biomedical gerontology and mitochondrial medicine. |
本系統中英文摘要資訊取自各篇刊載內容。