Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells
Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells
复制标题
DOI：
10.1093/hmg/ddp503
复制
发表时间：
2010-01-15
影响因子：
3.5
通讯作者：
Manfredi, G.
中科院分区：
文献类型：
--
作者：
D'Aurelio, M.;Vives-Bauza, C.;Manfredi, G.
线粒体DNA（mtDNA）编码ATP酶亚基6（ATP 6）的突变与可变疾病表达相关，范围从成人发作的神经病、共济失调和色素性视网膜炎（NARP）到致命的儿童母系遗传的Leigh综合征（MILS）。表型变异在很大程度上归因于mtDNA异质性。然而，突变mtDNA的水平和疾病的严重程度之间往往存在差异。因此，NARP/MILS的遗传缺陷、生物能量损害和临床结果之间的相关性仍有待阐明。我们研究了来自5名携带不同ATP 6突变的患者的胞质杂交体的生物能量学：3名携带T8993 G，1名携带T8993 C，1名携带T9176 G突变。不仅在不同的ATP 6突变体之间，而且在携带相同的T8993 G突变的品系之间，生物能量缺陷变化很大。最严重的ATP合成障碍的突变体表现出缺陷的呼吸和分解的呼吸链复合物。这表明呼吸链缺陷调节NARP/MILS细胞中的生物能量损伤。对来自不同突变细胞系的整个mtDNA进行测序，确定了结构基因的变异，导致氨基酸变化，使呼吸链不稳定。总之，这些结果表明，mtDNA背景在调节NARP/MILS的生化缺陷和临床结果中起着重要作用。
Mutations in the mitochondrial DNA (mtDNA) encoded subunit 6 of ATPase (ATP6) are associated with variable disease expression, ranging from adult onset neuropathy, ataxia and retinitis pigmentosa (NARP) to fatal childhood maternally inherited Leigh's syndrome (MILS). Phenotypical variations have largely been attributed to mtDNA heteroplasmy. However, there is often a discrepancy between the levels of mutant mtDNA and disease severity. Therefore, the correlation among genetic defect, bioenergetic impairment and clinical outcome in NARP/MILS remains to be elucidated. We investigated the bioenergetics of cybrids from five patients carrying different ATP6 mutations: three harboring the T8993G, one with the T8993C and one with the T9176G mutation. The bioenergetic defects varied dramatically, not only among different ATP6 mutants, but also among lines carrying the same T8993G mutation. Mutants with the most severe ATP synthesis impairment showed defective respiration and disassembly of respiratory chain complexes. This indicates that respiratory chain defects modulate the bioenergetic impairment in NARP/MILS cells. Sequencing of the entire mtDNA from the different mutant cell lines identified variations in structural genes, resulting in amino acid changes that destabilize the respiratory chain. Taken together, these results indicate that the mtDNA background plays an important role in modulating the biochemical defects and clinical outcome in NARP/MILS.