Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease with mitochondrial DNA (mtDNA) alterations and is caused by mutations in the nuclear gene encoding thymidine phosphorylase (TP). The cardinal clinical manifestations are ptosis, ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. Skeletal muscle shows mitochondrial abnormalities, including ragged-red fibers and cytochrome c oxidase deficiency, together with mtDNA depletion, multiple deletions or both. In MNGIE patients, TP mutations cause a loss-of-function of the cytosolic enzyme, TP. As a direct consequence of the TP defect, thymidine metabolism is altered. High blood levels of this nucleoside are likely to lead to mtDNA defects even in cells that do not express TP, such as skeletal muscle. We hypothesize that high concentrations of thymidine affect dNTP (deoxyribonucleoside triphosphate) metabolism in mitochondria more than in cytosol or nuclei, because mitochondrial dNTPs depend mainly on the thymidine salvage pathway, whereas nuclear dNTPs depend mostly on de novo pathway. The imbalance in the mitochondrial dNTP homeostasis affects mtDNA replication, leading to mitochondrial dysfunction.

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线粒体神经胃肠脑肌病和胸苷代谢：结果和假设

线粒体神经胃肠脑肌病 (MNGIE) 是一种常染色体隐性遗传病，具有线粒体 DNA (mtDNA) 改变，由编码胸苷磷酸化酶 (TP) 的核基因突变引起。主要临床表现是上睑下垂、眼肌麻痹、胃肠动力障碍、恶病质、周围神经病变和白质脑病。骨骼肌显示线粒体异常，包括参差不齐的红色纤维和细胞色素 c 氧化酶缺乏，以及 mtDNA 耗竭、多重缺失或两者兼而有之。在 MNGIE 患者中，TP 突变会导致胞质酶 TP 的功能丧失。作为 TP 缺陷的直接后果，胸苷代谢发生改变。即使在不表达 TP 的细胞（如骨骼肌）中，这种核苷的高血液水平也可能导致 mtDNA 缺陷。我们假设高浓度的胸苷对线粒体中 dNTP（脱氧核糖核苷三磷酸）代谢的影响大于在细胞质或细胞核中的代谢，因为线粒体 dNTP 主要依赖于胸苷补救途径，而核 dNTP 主要依赖于从头途径。线粒体 dNTP 稳态失衡会影响 mtDNA 复制，导致线粒体功能障碍。