Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy
Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy
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DOI：
10.1038/ng751
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发表时间：
2001-11-01
期刊：
影响因子：
30.8
通讯作者：
Elpeleg, O
中科院分区：
文献类型：
--
作者：
Saada, A;Shaag, A;Elpeleg, O
线粒体脱氧核糖核苷酸 (dNTP) 池与胞质池分离，因为线粒体内膜对带电分子是不可渗透的。线粒体库通过专用转运蛋白输入胞质 dNTP (1,2) 或通过回收线粒体内的脱氧核苷来维持；显然，线粒体中不存在 dNTP 从头合成途径的酶。在非复制细胞中，胞浆 dNTP 合成下调，mtDNA 合成仅依赖于线粒体挽救途径酶，即脱氧核糖核苷激酶。四种人类脱氧核糖核苷激酶中的两种脱氧鸟苷激酶 (dGK) 和胸苷激酶 2 (TK2) 在线粒体中表达 (3-6)。人 dGK 有效磷酸化脱氧鸟苷和脱氧腺苷，而 TK2 磷酸化脱氧胸苷、脱氧胞苷和脱氧尿苷。在这里，我们在四个婴儿期患上毁灭性肌病和肌肉线粒体 DNA 耗竭的个体中发现了 TK2 的两个突变，组氨酸 90 突变为天冬酰胺，异亮氨酸 181 突变为天冬酰胺。在这些个体中，肌肉线粒体中的 TK2 活性降低至健康对照个体平均值的 14-45%。 TK2 突变代表了线粒体 DNA 耗竭的新病因，强调了线粒体 dNTP 库在线粒体耗竭发病机制中的重要性。
The mitochondrial deoxyribonucleotide (dNTP) pool is separated from the cytosolic pool because the mitochondria inner membrane is impermeable to charged molecules. The mitochondrial pool is maintained by either import of cytosolic dNTPs through dedicated transporters(1,2) or by salvaging deoxynucleasides within the mitochondria; apparently, enzymes of the de novo dNTP synthesis pathway are not present in the mitochondria. In non-replicating cells, where cytosolic dNTP synthesis is downregulated, mtDNA synthesis depends solely on the mitochondrial salvage pathway enzymes, the deoxyribonucleosides kinases. Two of the four human deoxyribonucleoside kinases, deoxyguanosine kinase (dGK) and thymidine kinase-2 (TK2), are expressed in mitochondria(3-6). Human dGK efficiently phosphorylates deoxyguanosine and deoxyadenosine, whereas TK2 phosphorylates deoxythymidine, deoxycytidine and deoxyuridine. Here we identify two mutations in TK2, histidine 90 to asparagine and isoleucine 181 to asparagine, in four individuals who developed devastating myopathy and depletion of muscular mitochondrial DNA in infancy. In these individuals, the activity of TK2 in muscle mitochondria is reduced to 14-45% of the mean value in healthy control individuals. Mutations in TK2 represent a new etiology for mitochondrial DNA depletion, underscoring the importance of the mitochondrial dNTP pool in the pathogenesis of mitochondrial depletion.