Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice
Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice
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DOI：
10.1093/hmg/ddn401
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发表时间：
2009-02-15
影响因子：
3.5
通讯作者：
Hirano, Michio
中科院分区：
文献类型：
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作者：
Lopez, Luis C.;Akman, Hasan O.;Hirano, Michio
DNA的复制和修复需要脱氧核苷三磷酸前体的平衡池。多年来，这一概念已被体外研究证明，但需要体内模型来证明其与多细胞生物和人类疾病的相关性。因此，我们产生了胸苷磷酸化酶（TP）和尿苷磷酸化酶（UP）双敲除（TP-/-UP-/-）小鼠，其显示出严重的TP缺乏、组织中胸苷和脱氧尿苷增加以及线粒体脱氧胸苷三磷酸升高。作为核苷酸库失衡的后果，突变小鼠的大脑出现线粒体DNA部分缺失、呼吸链复合体缺陷和脑病。这些发现在很大程度上解释了线粒体神经胃肠脑病（MNGIE）的发病机制，MNGIE是第一个与体细胞DNA不稳定相关的遗传性人类核苷代谢障碍。
Replication and repair of DNA require equilibrated pools of deoxynucleoside triphosphate precursors. This concept has been proven by in vitro studies over many years, but in vivo models are required to demonstrate its relevance to multicellular organisms and to human diseases. Accordingly, we have generated thymidine phosphorylase (TP) and uridine phosphorylase (UP) double knockout (TP-/-UP-/-) mice, which show severe TP deficiency, increased thymidine and deoxyuridine in tissues and elevated mitochondrial deoxythymidine triphosphate. As consequences of the nucleotide pool imbalances, brains of mutant mice developed partial depletion of mtDNA, deficiencies of respiratory chain complexes and encephalopathy. These findings largely account for the pathogenesis of mitochondrial neurogastrointestinal encephalopathy (MNGIE), the first inherited human disorder of nucleoside metabolism associated with somatic DNA instability.