Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla 41013, Spain.
Department of Neurology, Uniklinikum C. G. Carus, Dresden, Germany.
Biochim Biophys Acta Mol Cell Res. 2019 May;1866(5):861-881. doi: 10.1016/j.bbamcr.2019.02.010. Epub 2019 Feb 22.
Mitochondrial diseases are a group of rare heterogeneous genetic disorders caused by total or partial mitochondrial dysfunction. They can be caused by mutations in nuclear or mitochondrial DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most common mitochondrial disorders caused by point mutations in mtDNA. It is mainly caused by the m.8344A > G mutation in the tRNA (UUR) gene of mtDNA (MT-TK gene). This mutation affects the translation of mtDNA encoded proteins; therefore, the assembly of the electron transport chain (ETC) complexes is disrupted, leading to a reduced mitochondrial respiratory function. However, the molecular pathogenesis of MERRF syndrome remains poorly understood due to the lack of appropriate cell models, particularly in those cell types most affected in the disease such as neurons. Patient-specific induced neurons (iNs) are originated from dermal fibroblasts derived from different individuals carrying the particular mutation causing the disease. Therefore, patient-specific iNs can be used as an excellent cell model to elucidate the mechanisms underlying MERRF syndrome. Here we present for the first time the generation of iNs from MERRF dermal fibroblasts by direct reprograming, as well as a series of pathophysiological characterizations which can be used for testing the impact of a specific mtDNA mutation on neurons and screening for drugs that can correct the phenotype.
线粒体疾病是一组由线粒体功能完全或部分异常引起的罕见异质性遗传疾病。它们可能由核 DNA 或线粒体 DNA（mtDNA）的突变引起。肌阵挛性癫痫伴破碎红纤维（MERRF）综合征是由 mtDNA 点突变引起的最常见的线粒体疾病之一。它主要由 mtDNA（MT-TK 基因）中的 tRNA（UUR）基因 m.8344A>G 突变引起。该突变影响 mtDNA 编码蛋白的翻译；因此，电子传递链（ETC）复合物的组装被破坏，导致线粒体呼吸功能降低。然而，由于缺乏合适的细胞模型，特别是在疾病中受影响最大的细胞类型（如神经元）中，MERRF 综合征的分子发病机制仍知之甚少。患者特异性诱导神经元（iNs）来源于携带导致疾病的特定突变的不同个体的皮肤成纤维细胞。因此，患者特异性 iNs 可作为阐明 MERRF 综合征发病机制的优秀细胞模型。在这里，我们首次通过直接重编程生成了源自 MERRF 皮肤成纤维细胞的 iNs，并对其进行了一系列病理生理学特征分析，可用于测试特定 mtDNA 突变对神经元的影响，筛选可纠正表型的药物。
