粒線體疾病與粒線體DNA缺乏症候群

Mitochondrial Disease and Mitochondrial DNA Depletion Syndromes

黃錦章(Chin-Chang Huang) ； 徐昌鴻(Chang-Huang Hsu)

《Acta Neurologica Taiwanica》 18卷4期 (2009/12) Pp. 287-295

https://doi.org/10.29819/ANT.200912.0007

摘要

粒線體是一種細胞質內的雙層膜構造，主要的功能在於提供有氣呼吸的能量來源，像是Krebs cycle、脂肪酸β型氣化作用和氣化磷酸化作用。粒線體的密度在每種組織內都不一樣，氣化磷酸化越旺盛的地方粒線體量就越多，粒線體擁有自己的DNA負責部分的氣化磷酸化的作用。拉線體疾病的產生可導因於粒線體DNA的問題或是細胞核DNA的缺陷。
人類粒線體DNA包含了22 tRNAs、2 rRNAs和13 mRNAs。粒線體DNA病變包括粒線體點突變、DNA斷損或是粒線體DNA數量的缺乏。遺傳的模式包括自發性發生、母系遺傳或符合孟德爾遺傳定律。粒線體DNA缺乏症候群是粒線體DNA數量上的缺乏所導致，原因來自於維持粒線體完整及DNA複製最重要的因子一體染色體強細胞密碼因子功能上的喪失。此症候群的相關疾病症候群包括：漸進性外眼肌麻痺(PEO)、肌肉病變、粒線體神經胃腸腦病變症候群(MNGIE)、感覺型共濟失調神經病變合併構音障礙及眼球肌運動麻痺症候群(SANDO)和肝腦病變。相關基因缺損可以分成兩大類：第一類是作用在粒線體DNA的複製途徑上的塞因缺損例如POLG、POLG2和Twinkle helicase基因。另一類則是提供DNA合成原料deoxynucleotide triphosphate Pool的基因缺損有關包括：ANT1(adenine nucleotide translocator 1)、TK2(thymidine kinase 2)、TP(thymidine Phosphorylase)、DGUOK(deoxyguanosine kinase)、SUCLA2(ADP-forming succinyl-CoA syntlietase ligase)、MPV17和RRM2B(P53-controlled ribonucleotide reductase)。未來的研究將會著重在細胞核DNA與粒線體DNA的交互作用上。

關鍵字

粒線體疾病 ； 粒線體基因 ； 粒線體DNA缺乏症 ； DNA複製 ； 進行性外眼肌麻痺症

並列摘要

Mitochondria is an intracellular double membrane-bound structure and it can provide energy for intracellular metabolism. The metabolism includes Krebs cycle, β-oxidation and lipid synthesis. The density of mitochondria is different in various tissues dependent upon the demands of oxidative phosphorylation. Mitochondrial diseases can occur by defects either in mitochondrial DNA or nuclear DNA. Human mitochondrial DNA (mtDNA) encoding for 22 tRNAs, 2 rRNAs and 13 mRNAs that are translated in the mitochondria. Mitochondrial genetic diseases are most resulted from defects in the mtDNA which may be point mutations, deletions, or mitochondrial DNA depletion. These patterns of inheritance in mitochondrial diseases include sporadic, maternally inherited, or of Mendelian inheritance. Mitochondrial DNA depletion is caused by defects in the nuclear genes that are responsible for maintenance of integrity of mtDNA or deoxyribonucelotide pools and mtDNA biogenesis. The mtDNA depletion syndrome (MDS) includes the following categories: progressive external ophthalmoplegia (PEO), predominant myopathy, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), sensory-ataxic neuropathy, dysarthria, and ophthalmoplegia (SANDO) and hepato-encephalopathy. The most common tissues or organs involved in MDS and related disorders include the brain, liver and muscles. These involved genes are divided into two groups including 1) DNA polymerase gamma. (POLG, POLG2) and Twinkle genes whose products function directly at the mtDNA replication fork, and 2) adenine nucleotide translocator 1, thymidine phosphorylase, thymidine kinase 2, deoxyguanosine kinase, ADP-forming succinyl-CoA synthetase ligase, MPV17 whose products supply the mitochondria with deoxyribonucleotide triphosphate pools needed for mtDNA replication, and possible mutation in the RRM2B gene. The development has provided new information about the importance of the biosynthetic pathway of the nucleotides for mtDNA replication. Further investigation on the understatanding between the nuclear and mitochondrial genomes is expected.

並列關鍵字

Mitochondrial disease ； Molecular genetics ； MtDNA depletion syndrome ； DNA replication ； Progressive external ophthalmoplegia