Povea-Cabello Suleva, Villanueva-Paz Marina, Suárez-Rivero Juan M, Álvarez-Córdoba Mónica, Villalón-García Irene, Talaverón-Rey Marta, Suárez-Carrillo Alejandra, Munuera-Cabeza Manuel, Sánchez-Alcázar José A
Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Seville, Spain.
Instituto de Investigación Biomédica de Málaga, Departamento de Farmacología y Pediatría, Facultad de Medicina, Universidad de Málaga, Málaga, Spain.
Front Genet. 2021 Jan 12;11:610764. doi: 10.3389/fgene.2020.610764. eCollection 2020.
Mitochondrial diseases are a heterogeneous group of rare genetic disorders that can be caused by mutations in nuclear (nDNA) or mitochondrial DNA (mtDNA). Mutations in mtDNA are associated with several maternally inherited genetic diseases, with mitochondrial dysfunction as a main pathological feature. These diseases, although frequently multisystemic, mainly affect organs that require large amounts of energy such as the brain and the skeletal muscle. In contrast to the difficulty of obtaining neuronal and muscle cell models, the development of induced pluripotent stem cells (iPSCs) has shed light on the study of mitochondrial diseases. However, it is still a challenge to obtain an appropriate cellular model in order to find new therapeutic options for people suffering from these diseases. In this review, we deepen the knowledge in the current models for the most studied mt-tRNA mutation-caused mitochondrial diseases, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers) syndromes, and their therapeutic management. In particular, we will discuss the development of a novel model for mitochondrial disease research that consists of induced neurons (iNs) generated by direct reprogramming of fibroblasts derived from patients suffering from MERRF syndrome. We hypothesize that iNs will be helpful for mitochondrial disease modeling, since they could mimic patient's neuron pathophysiology and give us the opportunity to correct the alterations in one of the most affected cellular types in these disorders.
线粒体疾病是一组由核基因（nDNA）或线粒体DNA（mtDNA）突变引起的罕见遗传性疾病，具有异质性。mtDNA突变与几种母系遗传的遗传病相关，其主要病理特征为线粒体功能障碍。这些疾病虽然常常累及多个系统，但主要影响需要大量能量的器官，如大脑和骨骼肌。与获取神经元和肌肉细胞模型的困难形成对比的是，诱导多能干细胞（iPSC）的发展为线粒体疾病的研究带来了曙光。然而，要获得合适的细胞模型以找到针对这些疾病患者的新治疗方案，仍然是一项挑战。在本综述中，我们深入探讨了目前针对研究最多的由线粒体tRNA突变引起的线粒体疾病——线粒体脑肌病伴乳酸血症和卒中样发作（MELAS）以及肌阵挛性癫痫伴破碎红纤维（MERRF）综合征的模型，以及它们的治疗管理。特别是，我们将讨论一种用于线粒体疾病研究的新型模型的开发，该模型由直接重编程来自MERRF综合征患者的成纤维细胞产生的诱导神经元（iN）组成。我们推测iN将有助于线粒体疾病建模，因为它们可以模拟患者神经元的病理生理学，并为我们提供机会纠正这些疾病中最受影响的细胞类型之一的改变。
