CoQ(10) deficiencies and MNGIE: two treatable mitochondrial disorders.
CoQ(10) deficiencies and MNGIE: two treatable mitochondrial disorders.
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DOI：
10.1016/j.bbagen.2012.01.006
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发表时间：
2012-05
影响因子：
3
通讯作者：
Quinzii, Catarina M.
中科院分区：
文献类型：
--
作者：
Hirano, Michio;Garone, Caterina;Quinzii, Catarina M.
虽然已经确定了许多线粒体疾病的致病突变，但很少有疾病修饰治疗方法可用。可治疗的线粒体疾病的两个实例是辅酶Q10（CoQ10或泛醌）缺乏和线粒体神经胃肠脑肌病（MNGIE）。在这里，我们描述了辅酶Q10缺乏症和MNGIE的临床和分子特征，并解释了如何理解其病理机制导致合理的治疗。主要辅酶Q10缺乏症，由于泛醌生物合成所需的基因突变，和继发性缺陷，由遗传缺陷造成的不直接相关的辅酶Q10生物合成，往往改善辅酶Q10补充剂。辅酶Q10缺乏症的体外和体内研究揭示了可能导致患者表型差异和对治疗的可变反应的生化改变。与CoQ10的异质性缺陷相反，MNGIE是一种单一的常染色体隐性遗传疾病，由于编码胸苷磷酸化酶（TP）的TYMP基因突变。在MNGIE中，TP活性的丧失导致核苷胸苷和脱氧尿苷的毒性积累，这些核苷胸苷和脱氧尿苷通过线粒体嘧啶补救途径并入，并导致脱氧核苷三磷酸池失衡，这反过来又导致mtDNA不稳定。异基因造血干细胞移植恢复TP活性和清除毒性代谢产物是治疗MNGIE的一种有希望的方法。辅酶Q10缺乏症和MNGIE证明了通过替代缺乏的代谢物或通过消除过量的毒性分子来治疗特定线粒体疾病的可行性。CoQ10缺乏和MNGIE的研究说明了理解线粒体疾病的致病机制如何能够导致有意义的治疗。
Although causative mutations have been identified for numerous mitochondrial disorders, few disease-modifying treatments are available. Two examples of treatable mitochondrial disorders are coenzyme Q10 (CoQ10 or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Here, we describe clinical and molecular features of CoQ10 deficiencies and MNGIE and explain how understanding their pathomechanisms have led to rationale therapies. Primary CoQ10 deficiencies, due to mutations in genes required for ubiquinone biosynthesis, and secondary deficiencies, caused by genetic defects not directly related to CoQ10 biosynthesis, often improve with CoQ10 supplementation. In vitro and in vivo studies of CoQ10 deficiencies have revealed biochemical alterations that may account for phenotypic differences among patients and variable responses to therapy. In contrast to the heterogeneous CoQ10 deficiencies, MNGIE is a single autosomal recessive disease due to mutations in the TYMP gene encoding thymidine phosphorylase (TP). In MNGIE, loss of TP activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which, in turn cause mtDNA instability. Allogeneic hematopoetic stem cell transplantation to restore TP activity and eliminate toxic metabolites is a promising therapy for MNGIE. CoQ10 deficiencies and MNGIE demonstrate the feasibility of treating specific mitochondrial disorders through replacement of deficient metabolites or via elimination of excessive toxic molecules. Studies of CoQ10 deficiencies and MNGIE illustrate how understanding the pathogenic mechanisms of mitochondrial diseases can lead to meaningful therapies.
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