ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis

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...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2008-05, Vol.320 (5876), p.661-664
Main Authors: Ishikawa, Kaori, Takenaga, Keizo, Akimoto, Miho, Koshikawa, Nobuko, Yamaguchi, Aya, Imanishi, Hirotake, Nakada, Kazuto, Honma, Yoshio, Hayashi, Jun-Ichi
Format: Article
Language:English
Subjects:
Acetylcysteine - pharmacology
Animals
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Cell lines
Cell physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Cells
DNA, Mitochondrial
DNA, Neoplasm
Electron Transport Complex I - genetics
Electron Transport Complex I - metabolism
Free Radical Scavengers - pharmacology
Fundamental and applied biological sciences. Psychology
Genetic mutation
HeLa Cells
Humans
Hybrid Cells
Metastasis
Mice
Mitochondrial DNA
Molecular and cellular biology
Mutation
Myeloid cells
NADH Dehydrogenase - genetics
NADH Dehydrogenase - metabolism
Neoplasm Metastasis - genetics
NIH 3T3 cells
Oncology
Reactive oxygen species
Reactive Oxygen Species - metabolism
Tumor cell line
Tumors
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1156906