Prigione Alessandro
Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Str. 10, 13125, Berlin-Buch, Germany,
Methods Mol Biol. 2015;1265:349-56. doi: 10.1007/978-1-4939-2288-8_24.
Defects in mitochondrial DNA (mtDNA) are a frequent cause of genetic disease, with a minimum prevalence of 1 in 5,000 individuals. These disorders often present with neurological features, exhibit high clinical variability, and lack effective treatments. Viable disease models would be critical to elucidate the genotype/phenotype relationship and improve disease management. However, the peculiarities of mitochondrial genetics have hampered the generation of animal models, and current cellular models do not carry the nuclear background of the patients and do not exhibit the features of differentiated cells such as postmitotic neurons. Hence, the development of innovative modeling systems is highly needed in order to correctly address the interplay between the nuclear and mitochondrial genome within the appropriate human target cell types. The establishment of induced pluripotent stem cells (iPSCs) from patients affected by mtDNA disorders thus appears as a promising approach. Patient-derived iPSCs would contain both the original nuclear and mitochondrial DNA of the patients and would be capable of differentiating into any cell type of the body, including postmitotic neurons. Here we discuss the potential advantages and critical challenges for the application of the iPSC technology for modeling debilitating mtDNA diseases.
线粒体DNA（mtDNA）缺陷是遗传疾病的常见病因，最低患病率为每5000人中就有1人。这些疾病通常表现出神经学特征，临床变异性高，且缺乏有效的治疗方法。可行的疾病模型对于阐明基因型/表型关系和改善疾病管理至关重要。然而，线粒体遗传学的特殊性阻碍了动物模型的建立，目前的细胞模型不具备患者的核背景，也不表现出有丝分裂后神经元等分化细胞的特征。因此，迫切需要开发创新的建模系统，以便在合适的人类靶细胞类型中正确解决核基因组与线粒体基因组之间的相互作用。从受mtDNA疾病影响的患者中建立诱导多能干细胞（iPSC）因此似乎是一种有前途的方法。患者来源的iPSC将包含患者原始的核DNA和线粒体DNA，并能够分化为身体的任何细胞类型，包括有丝分裂后神经元。在这里，我们讨论了将iPSC技术应用于模拟使人衰弱的mtDNA疾病的潜在优势和关键挑战。
