Lombès Anne, Auré Karine, Bellanné-Chantelot Christine, Gilleron Mylène, Jardel Claude
Inserm Institut Cochin U1016, CNRS UMR 8104, 24 rue du Fb St Jacques, Paris F-75014, France; Université Paris-Descartes-Paris5, Paris F-75014, France; AP-HP, Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, GHU Pitié-Salpêtrière, Paris F-75651, France.
Inserm Institut Cochin U1016, CNRS UMR 8104, 24 rue du Fb St Jacques, Paris F-75014, France; AP-HP, Hôpital Ambroise Paré, Service d'explorations fonctionnelles, Boulogne-Billancourt F-92100, France; Université Versailles-Saint-Quentin en Yvelines, Faculté de Médecine, F-78180, France.
Biochimie. 2014 May;100:171-6. doi: 10.1016/j.biochi.2013.08.012. Epub 2013 Aug 20.
Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed. Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.
人类线粒体疾病，定义为由于线粒体氧化磷酸化缺陷导致的疾病，就表型和遗传病因而言，代表了一大类非常多样的疾病。它们存在许多未解决的问题，本文对此不作全面分析。我们在此主要关注靶向组织多样性背后的机制，这是这些疾病众多表型表达中的一个重要组成部分。本文将对基因型/表型表达的可重复性、修饰因子的存在以及组织表达受限模式的潜在原因进行综述。特别强调异质性，这是线粒体疾病的一个特殊特征，定义为突变型和野生型线粒体DNA分子在细胞内共存。它的存在使得线粒体DNA群体在有丝分裂过程中发生不等分离，从而导致突变负荷在组织中的分布不均一。人类线粒体DNA常见有害突变的组织分布各不相同，但对于给定的突变是可重复的，这表明分离不是一个随机过程。尽管在动物模型方面取得了最新进展，但其程度和机制基本上仍不清楚。
