Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.
Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10528-33. doi: 10.1073/pnas.1202367109. Epub 2012 Jun 11.
It has been hypothesized that respiration defects caused by accumulation of pathogenic mitochondrial DNA (mtDNA) mutations and the resultant overproduction of reactive oxygen species (ROS) or lactates are responsible for aging and age-associated disorders, including diabetes and tumor development. However, there is no direct evidence to prove the involvement of mtDNA mutations in these processes, because it is difficult to exclude the possible involvement of nuclear DNA mutations. Our previous studies resolved this issue by using an mtDNA exchange technology and showed that a G13997A mtDNA mutation found in mouse tumor cells induces metastasis via ROS overproduction. Here, using transmitochondrial mice (mito-mice), which we had generated previously by introducing G13997A mtDNA from mouse tumor cells into mouse embryonic stem cells, we provide convincing evidence supporting part of the abovementioned hypothesis by showing that G13997A mtDNA regulates diabetes development, lymphoma formation, and metastasis--but not aging--in this model.
有人假设，呼吸缺陷是由致病性线粒体 DNA（mtDNA）突变的积累以及由此产生的活性氧（ROS）或乳酸的过度产生引起的，这与衰老和与年龄相关的疾病有关，包括糖尿病和肿瘤的发展。然而，目前尚无直接证据证明 mtDNA 突变参与了这些过程，因为很难排除核 DNA 突变的可能参与。我们之前的研究通过使用 mtDNA 交换技术解决了这个问题，并表明在小鼠肿瘤细胞中发现的 G13997A mtDNA 突变通过 ROS 过度产生诱导转移。在这里，我们使用之前通过将来自小鼠肿瘤细胞的 G13997A mtDNA 引入小鼠胚胎干细胞而生成的递线粒体小鼠（mito-mice），通过显示 G13997A mtDNA 调节糖尿病的发展、淋巴瘤的形成和转移——而不是衰老——在这个模型中，为上述部分假设提供了令人信服的证据。
