IDENTIFICATION OF ATAXIA-ASSOCIATED mtDNA MUTATIONS (m.4052T>C and m.9035T>C) AND EVALUATION OF THEIR PATHOGENICITY IN TRANSMITOCHONDRIAL CYBRIDS
IDENTIFICATION OF ATAXIA-ASSOCIATED mtDNA MUTATIONS (m.4052T>C and m.9035T>C) AND EVALUATION OF THEIR PATHOGENICITY IN TRANSMITOCHONDRIAL CYBRIDS
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DOI：
10.1002/mus.21355
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发表时间：
2009-09-01
期刊：
影响因子：
3.4
通讯作者：
Tarnopolsky, Mark A.
中科院分区：
文献类型：
--
作者：
Sikorska, Marianna;Sandhu, Jagdeep K.;Tarnopolsky, Mark A.
在一个患有母系遗传的认知发育迟缓、学习障碍和进行性共济失调的家系中发现了两个同质性mtDNA点突变9035 T>C和4452 T>C，利用线粒体胞质杂种评估了这两个点突变的潜在致病性。我们证实tRNA（Met）的4452 T>C转换代表多态性;然而，ATP 6基因的9035 T>C转换是导致F（0）-ATP酶缺陷的原因。因此，突变胞质杂交体具有降低的寡霉素敏感性ATP水解活性。它们的ATP含量不到稳态的一半，活性氧（ROS）的基础水平高出近8倍。突变的胞质杂种不能科普额外的损伤，即，葡萄糖剥夺或叔丁基过氧化氢，并且它们屈服于凋亡或坏死细胞死亡。这两种结果都被抗氧化剂辅酶Q（10）和维生素E所阻止，这表明异常高水平的ROS是细胞死亡的触发因素。总之，主要的代谢缺陷，即，9035 T>C突变导致的能量缺乏和ROS负担，可能是该家系临床症状发生的原因。此外，抗氧化治疗可能有助于这种疾病的管理。肌肉神经40：381-394，2009
The potential pathogenicity of two homoplasmic mtDNA point mutations, 9035T>C and 4452T>C, found in a family afflicted with maternally transmitted cognitive developmental delay, learning disability, and progressive ataxia was evaluated using transmitochondrial cybrids. We confirmed that the 4452T>C transition in tRNA(Met) represented a polymorphism; however, 9035T>C conversion in the ATP6 gene was responsible for a defective F(0)-ATPase. Accordingly, mutant cybrids had a reduced oligomycin-sensitive ATP hydrolyzing activity. They had less than half of the steady-state content of ATP and nearly an 8-fold higher basal level of reactive oxygen species (ROS). Mutant cybrids were unable to cope with additional insults, i.e., glucose deprivation or tertiary-butyl hydroperoxide, and they succumbed to either apoptotic or necrotic cell death. Both of these outcomes were prevented by the antioxidants CoQ(10) and vitamin E, suggesting that the abnormally high levels of ROS were the triggers of cell death. In conclusion, the principal metabolic defects, i.e., energy deficiency and ROS burden, resulted from the 9035T>C mutation and could be responsible for the development of clinical symptoms in this family. Furthermore, antioxidant therapy might prove helpful in the management of this disease. Muscle Nerve 40: 381-394, 2009