ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis

doi:10.1126/science.1156906

Account Information

Guest Alerts | Access Rights | My Account | Sign In

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

Abstract: Mutations in mitochondrial DNA (mtDNA) occur at high frequencyin human tumors, but whether these mutations alter tumor cellbehavior has been unclear. We used cytoplasmic hybrid (cybrid)technology to replace the endogenous mtDNA in a mouse tumorcell line that was poorly metastatic with mtDNA from a cellline that was highly metastatic, and vice versa. Using assaysof metastasis in mice, we found that the recipient tumor cellsacquired the metastatic potential of the transferred mtDNA.The mtDNA conferring high metastatic potential contained G13997Aand 13885insC mutations in the gene encoding NADH (reduced formof nicotinamide adenine dinucleotide) dehydrogenase subunit6 (ND6). These mutations produced a deficiency in respiratorycomplex I activity and were associated with overproduction ofreactive oxygen species (ROS). Pretreatment of the highly metastatictumor cells with ROS scavengers suppressed their metastaticpotential in mice. These results indicate that mtDNA mutationscan contribute to tumor progression by enhancing the metastaticpotential 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.

To whom correspondence should be addressed. E-mail: jih45{at}sakura.cc.tsukuba.ac.jp

The editors suggest the following Related Resources on Science sites:

In Science Signaling

EDITORS' CHOICE
Medicine
Mitochondria as Drivers of Metastasis: Paula A. Kiberstis (6 May 2008)
Sci. Signal. 1 (18), ec162. [DOI: 10.1126/stke.118ec162]
| Abstract »