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ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis
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ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis
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Journal Article
ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis
2008
Overview
Mutations in mitochondrial DNA (mtDNA) occur at high frequency in human tumors, but whether these mutations alter tumor cell behavior has been unclear. We used cytoplasmic hybrid (cybrid) technology to replace the endogenous mtDNA in a mouse tumor cell line that was poorly metastatic with mtDNA from a cell line that was highly metastatic, and vice versa. Using assays of metastasis in mice, we found that the recipient tumor cells acquired the metastatic potential of the transferred mtDNA. The mtDNA conferring high metastatic potential contained G13997A and 13885insC mutations in the gene encoding NADH (reduced form of nicotinamide adenine dinucleotide) dehydrogenase subunit 6 (ND6). These mutations produced a deficiency in respiratory complex I activity and were associated with overproduction of reactive oxygen species (ROS). Pretreatment of the highly metastatic tumor cells with ROS scavengers suppressed their metastatic potential in mice. These results indicate that mtDNA mutations can contribute to tumor progression by enhancing the metastatic potential of tumor cells.
Publisher
American Association for the Advancement of Science,The American Association for the Advancement of Science
Subject
/ Animals
/ Antineoplastic Agents - pharmacology
/ Biological and medical sciences
/ Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
/ Cells
/ Electron Transport Complex I - genetics
/ Electron Transport Complex I - metabolism
/ Free Radical Scavengers - pharmacology
/ Fundamental and applied biological sciences. Psychology
/ genes
/ Humans
/ hybrids
/ Mice
/ Molecular and cellular biology
/ Mutation
/ NADH Dehydrogenase - genetics
/ NADH Dehydrogenase - metabolism
/ Neoplasm Metastasis - genetics
/ Oncology
/ Reactive Oxygen Species - metabolism
/ Tumors
