Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan ; Japan Society for the Promotion of Science, Tokyo, Japan ; Department of Molecular Immunology and Inflammation, National Center for Global Health and Medicine, Tokyo, Japan.
PLoS One. 2013 Sep 30;8(9):e75981. doi: 10.1371/journal.pone.0075981. eCollection 2013.
In mammalian species, mitochondrial DNA (mtDNA) with pathogenic mutations that induce mitochondrial respiration defects has been proposed to be involved in tumor phenotypes via induction of enhanced glycolysis under normoxic conditions (the Warburg effects). However, because both nuclear DNA and mtDNA control mitochondrial respiratory function, it is difficult to exclude the possible contribution of nuclear DNA mutations to mitochondrial respiration defects and the resultant expression of tumor phenotypes. Therefore, it is important to generate transmitochondrial cybrids sharing the same nuclear DNA background but carrying mtDNA with and without the mutations by using intercellular mtDNA transfer technology. Our previous studies isolated transmitochondrial cybrids and showed that specific mtDNA mutations enhanced tumor progression as a consequence of overproduction of reactive oxygen species (ROS). This study assessed whether mtDNA mutations inducing ROS overproduction always enhance tumor progression. We introduced mtDNA from senescence-accelerated mice P1 (SAMP1) into C57BL/6J (B6) mice-derived Lewis lung carcinoma P29 cells, and isolated new transmitochondrial cybrids (P29mtSAMP1 cybrids) that overproduced ROS. The inoculation of the cybrids into B6 mice unexpectedly showed that mtDNA from SAMP1 mice conversely induced tumor suppression. Moreover, the tumor suppression of P29mtSAMP1 cybrids in B6 mice occurred as a consequence of innate immune responses of the host B6 mice. Enzyme pretreatment experiments of P29mtSAMP1 cybrids revealed that some peptides encoded by mtDNA and expressed on the cell surface of P29mtSAMP1 cybrids induce increased IL-6 production from innate immune cells (dendritic cells) of B6 mice, and mediate augmented inflammatory responses around the tumor-inoculated environment. These observations indicate presence of a novel role of mtDNA in tumor phenotype, and provide new insights into the fields of mitochondrial tumor biology and tumor immunology.
在哺乳动物物种中，具有诱导线粒体呼吸缺陷的致病性突变的线粒体 DNA（mtDNA）被认为通过在正常氧条件下诱导增强的糖酵解（Warburg 效应）参与肿瘤表型。然而，由于核 DNA 和 mtDNA 都控制线粒体呼吸功能，因此很难排除核 DNA 突变对线粒体呼吸缺陷和肿瘤表型表达的可能贡献。因此，通过使用细胞间 mtDNA 转移技术生成具有相同核 DNA 背景但携带具有和不具有突变的 mtDNA 的传递线粒体细胞杂种是很重要的。我们之前的研究分离了传递线粒体细胞杂种，并表明特定的 mtDNA 突变会导致活性氧（ROS）的过度产生，从而增强肿瘤的进展。本研究评估了诱导 ROS 过度产生的 mtDNA 突变是否总是增强肿瘤的进展。我们将来自衰老加速小鼠 P1（SAMP1）的 mtDNA 引入 C57BL/6J（B6）小鼠来源的 Lewis 肺癌 P29 细胞中，并分离了新的传递线粒体细胞杂种（P29mtSAMP1 细胞杂种），其 ROS 过度产生。出乎意料的是，将这些细胞杂种接种到 B6 小鼠中表明，来自 SAMP1 小鼠的 mtDNA 反而诱导了肿瘤抑制。此外，B6 小鼠中 P29mtSAMP1 细胞杂种的肿瘤抑制是由于宿主 B6 小鼠的固有免疫反应所致。P29mtSAMP1 细胞杂种的酶预处理实验表明，P29mtSAMP1 细胞杂种表面表达的由 mtDNA 编码的一些肽诱导 B6 小鼠固有免疫细胞（树突状细胞）产生更多的 IL-6，并介导肿瘤接种环境周围炎症反应的增强。这些观察结果表明 mtDNA 在肿瘤表型中具有新的作用，并为线粒体肿瘤生物学和肿瘤免疫学领域提供了新的见解。
