Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.
Exp Anim. 2011;60(5):421-31. doi: 10.1538/expanim.60.421.
Mitochondrial genome (mtDNA) mutations and the resultant mitochondrial respiratory abnormalities are associated with a wide variety of disorders, such as mitochondrial diseases, neurodegenerative diseases, diabetes, and cancer, as well as aging. Generation of model animals carrying mutant mtDNAs is important for understanding the pathophysiological mechanisms of the mtDNA-based diseases. We have succeeded in generating three kinds of mice with pathogenic mutant mtDNAs, named "mito-mice," by the introduction of mitochondria carrying pathogenic mutant mtDNAs into mouse zygotes and mouse embryonic stem (ES) cells. In the case of mito-mice possessing the heteroplasmic state of wild-type mtDNA and pathogenic mtDNA with a large-scale deletion (ΔmtDNA, mito-miceΔ), a high load of ΔmtDNA induced mitochondrial respiration defects in various tissues, resulting in mitochondrial disease phenotypes, such as low body weight, lactic acidosis, ischemia, myopathy, heart block, deafness, male infertility, long-term memory defects, and renal failure. In this review, we summarize generation and clinical phenotypes of three types of mito-mice and we introduce several treatment trials for mitochondrial diseases using mito-miceΔ.
线粒体基因组（mtDNA）突变和由此产生的线粒体呼吸异常与多种疾病有关，如线粒体疾病、神经退行性疾病、糖尿病和癌症以及衰老。生成携带突变 mtDNA 的模型动物对于理解基于 mtDNA 的疾病的病理生理机制非常重要。我们通过将携带致病性突变 mtDNA 的线粒体引入小鼠受精卵和小鼠胚胎干细胞，成功生成了三种具有致病性突变 mtDNA 的小鼠，称为“mito-mice”。在具有野生型 mtDNA 和大片段缺失（ΔmtDNA，mito-miceΔ）的异质体状态的 mito-mice 中，高负荷的 ΔmtDNA 导致各种组织中的线粒体呼吸缺陷，导致线粒体疾病表型，如体重低、酸中毒、缺血、肌病、心脏阻滞、耳聋、男性不育、长期记忆缺陷和肾衰竭。在这篇综述中，我们总结了三种类型的 mito-mice 的生成和临床表型，并介绍了使用 mito-miceΔ 进行的几种线粒体疾病治疗试验。
