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Science 320 (5876): 661-664

Copyright © 2008 by the American Association for the Advancement of Science

ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis

Kaori Ishikawa,1,2,3* Keizo Takenaga,4,5* Miho Akimoto,5 Nobuko Koshikawa,4 Aya Yamaguchi,1 Hirotake Imanishi,1 Kazuto Nakada,1,2 Yoshio Honma,5 Jun-Ichi Hayashi1{dagger}

Abstract: 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.

1 Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
2 Tsukuba Advanced Research Alliance Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
3 Japan Society for the Promotion of Science (JSPS), 8 Ichibancho, Chiyoda-ku, Tokyo 102-8472, Japan.
4 Division of Chemotherapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan.
5 Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: jih45{at}

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   Abstract »    PDF »
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A. Shimizu, T. Mito, C. Hayashi, E. Ogasawara, R. Koba, I. Negishi, K. Takenaga, K. Nakada, and J.-I. Hayashi (2014)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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D. G. Corum, P. N. Tsichlis, and R. C. Muise-Helmericks (2014)
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   Abstract »    Full Text »    PDF »
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E. Lepage, E. Zampini, and N. Brisson (2013)
Plant Physiology 163, 867-881
   Abstract »    Full Text »    PDF »
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F. Zhou, Q. Shen, and F. X. Claret (2013)
J. Leukoc. Biol. 94, 423-429
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Elevated oxidative damage is correlated with reduced fitness in interpopulation hybrids of a marine copepod.
F. S. Barreto and R. S. Burton (2013)
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   Abstract »    Full Text »    PDF »
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N. Hempel, T. R. Bartling, B. Mian, and J. A. Melendez (2013)
Mol. Cancer Res. 11, 303-312
   Abstract »    Full Text »    PDF »
Relevance of Mitochondrial Genetics and Metabolism in Cancer Development.
G. Gasparre, A. M. Porcelli, G. Lenaz, and G. Romeo (2013)
Cold Spring Harb Perspect Biol 5, a011411
   Abstract »    Full Text »    PDF »
Mouse mtDNA mutant model of Leber hereditary optic neuropathy.
C. S. Lin, M. S. Sharpley, W. Fan, K. G. Waymire, A. A. Sadun, V. Carelli, F. N. Ross-Cisneros, P. Baciu, E. Sung, M. J. McManus, et al. (2012)
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   Abstract »    Full Text »    PDF »
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W. Zhou, L. A. Liotta, and E. F. Petricoin (2012)
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   Abstract »    Full Text »    PDF »
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C. Wanka, J. P. Steinbach, and J. Rieger (2012)
J. Biol. Chem. 287, 33436-33446
   Abstract »    Full Text »    PDF »
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V. Maximo, J. Lima, H. Prazeres, P. Soares, and M. Sobrinho-Simoes (2012)
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   Abstract »    Full Text »    PDF »
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O. Hashizume, A. Shimizu, M. Yokota, A. Sugiyama, K. Nakada, H. Miyoshi, M. Itami, M. Ohira, H. Nagase, K. Takenaga, et al. (2012)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Liu, L.-D. Wang, Y.-B. Sun, E.-M. Li, L.-Y. Xu, Y.-P. Zhang, Y.-G. Yao, and Q.-P. Kong (2012)
Mol. Biol. Evol. 29, 1255-1261
   Abstract »    Full Text »    PDF »
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W. Fan, C. S. Lin, P. Potluri, V. Procaccio, and D. C. Wallace (2012)
Genes & Dev. 26, 384-394
   Abstract »    Full Text »    PDF »
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M.-W. Kang, S. K. Kang, S. Choi, C. S. Lee, B. H. Jeon, and S. P. Lim (2012)
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   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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C. M. Haynes and D. Ron (2010)
J. Cell Sci. 123, 3849-3855
   Abstract »    Full Text »    PDF »
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J. Exp. Med. 207, 2297-2305
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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N. Koshikawa, J.-I. Hayashi, A. Nakagawara, and K. Takenaga (2009)
J. Biol. Chem. 284, 33185-33194
   Abstract »    Full Text »    PDF »
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L. Mao, K. J. Wertzler, S. C. Maloney, Z. Wang, N. S. Magnuson, and R. Reeves (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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D. C. Wallace and W. Fan (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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M. M. Lindroos, K. Majamaa, A. Tura, A. Mari, K. K. Kalliokoski, M. T. Taittonen, P. Iozzo, and P. Nuutila (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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A. M. Porcelli, A. Angelin, A. Ghelli, E. Mariani, A. Martinuzzi, V. Carelli, V. Petronilli, P. Bernardi, and M. Rugolo (2009)
J. Biol. Chem. 284, 2045-2052
   Abstract »    Full Text »    PDF »
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S. Maynard, S. H. Schurman, C. Harboe, N. C. de Souza-Pinto, and V. A. Bohr (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »

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