• 作者： 魏耀揮
• 作者服務機構： 陽明大學生化研究所及細胞暨分子生物學研究中心
• 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，在老人的身體組識中已發現在二十餘種的mtDNA突變。其中4,977 bp及7,436 bp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，在人類組識中的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識中。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 isexposed to a high steady-state level of reactive oxygen species and free radicals generated by the respiratorychain in mitochondria. Thus, it is much more vulnerable to oxidative damage and mutation than is nuclearDNA. In the past decade, more than two-dozen mutations of mtDNA have been observed in the somatictissues of aged individuals. Among them, the 4,977 bp and 7,436 bp deletions and the A3243G and A8344Gpoint 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%). Asidefrom 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 mitochon-drial myopathy and encephalomyopathy. The mutant mtDNA often coexists with the wild-type mtDNA inaffected tissues (a condition termed heteroplasmy). Usually the clinical severity of the disease is correlatedwith the proportion of the mutated mtDNA in the target tissues (usually>80%). The threshold of the mutantmtDNA 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 ofdistribution of the mutant mtDNA and the energy demand of the target tissues are important factors indetermining the pathological outcome of the mutation. The mutant mtDNA is usually widely distributed inthe body tissues of the patient, thereby leading to multi-system disorders, which are frequently seen inmitochondrial 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 ofmtDNA have also been found in the muscle and other affected tissues of elderly subjects and some patientswith mitochondrial myopathy. Moreover, recent work in our laboratory has shown that oxidative damage toDNA in affected tissues is significantly higher than that in normal tissues. It is now established thatmutation and oxidative damage of mtDNA are contributory factors to aging and that at high levels, theycause a fall of ATP supply below the threshold of energy needed by affected tissues in patients with mito-chondrial diseases. These advances have laid the foundation for the development of biomedical gerontologyand mitochondrial medicine.
• 中文關鍵字： Aging; myopathy; encephalomyopathy; mitochondrial DNA; mutation; depletion
• 英文關鍵字： --