Analysis of entire physiological roles of mammalian mtDNA by generation of mice carrying various pathogenic mutations

2011 Fiscal Year Final Research Report

• Project/Area Number: 19100007
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Laboratory animal science
• Research Institution: University of Tsukuba
• Principal Investigator: HAYASHI Jun-ichi 筑波大学, 生命環境系, 教授 (60142113)
• Co-Investigator(Kenkyū-buntansha): YONEKAWA Hiromichi 東京都医学研究機構, 東京都臨床医学総合研究所, 副所長 (30142110)
• Project Period (FY): 2007 – 2011
• Keywords: ミトコンドリアゲノム変異

Research Abstract

In this project we showed that specific pathogenic mutations that induce significant ROS production induced highly metastatic potentials in tumor cells. Moreover, when we introduced one of them into female germlines, and generated mito-mice with the mutation, mito-mice expressed diabetes and lymphoma development. On the contrary, we also found novel roles of specific polymorphic mtDNA mutations, which can be recognized and excluded by innate immune systems.

Research Products

• [Journal Article] Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development (2012)
  • Author(s): Osamu Hashizume, Akinori Shimizu, Mutsumi Yokota, Atsuko Sugiyama, Kazuto Nakada, Hiroyuki Miyoshi, Makiko Itami, Miki Ohira, Hiroki Nagase, Keizo Takenaga, and Jun-Ichi Hayashi
  • Journal Title: Proc. Natl. Acad. Sci Volume: (in Press)
  • Peer Reviewed
• [Journal Article] Mitochondrial DNA mutations regulate metastasis of human breast cancer cells (2011)
  • Author(s): Hirotake Imanishi, Keisuke Hattori, Reiko Wada, Kaori Ishikawa, Sayaka Fukuda, Keizo Takenaga, Kazuto Nakada, and Jun-Ichi Hayashi
  • Journal Title: PLoS One Volume: 6 Pages: e23401
  • URL: https://www.tulips.tsukuba.ac.jp/dspace/handle/2241/114066
  • Peer Reviewed
• [Journal Article] The innate immune system in host mice targets cells with allogenic mitochondrial DNA (2010)
  • Author(s): Kaori Ishikawa, Noriko Toyama-Sorimachi, Kazuto Nakada, Mami Morimoto, Hirotake Imanishi, Mariko Yoshizaki, Shigemi Sasawatari, Mamoru Niikura, Keizo Takenaga, Hiromichi Yonekawa, and Jun-Ichi Hayashi
  • Journal Title: J Exp. Med Volume: 207 Pages: 2297-2305
  • URL: https://www.tulips.tsukuba.ac.jp/dspace/handle/2241/107854
  • Peer Reviewed
• [Journal Article] Generation of trans-mitochondrial mito-mice by the introduction of a pathogenic G13997A mtDNA from highly metastatic lung carcinoma cells (2010)
  • Author(s): Mutsumi Yokota, Hiroshi Shitara, Osamu Hashizume, Kaori Ishikawa, Kazuto Nakada, Rie Ishii, Choji Taya, Keizo Takenaga, Hiromichi Yonekawa, and Jun-Ichi Hayashi
  • Journal Title: FEBS Lett Volume: 84 Pages: 3943-3948
  • URL: https://www.tulips.tsukuba.ac.jp/dspace/handle/2241/106654
  • Peer Reviewed
• [Journal Article] Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1alpha gene transcription via phosphatidylinositol3-kinase-Akt/protein kinase C/histone deacetylase pathway (2009)
  • Author(s): Nobuko Koshikawa, Jun-Ichi Hayashi, Akira Nakagawara, and Keizo Takenaga
  • Journal Title: J. Biol. Chem Volume: 284 Pages: 33185-33194
  • Peer Reviewed
• [Journal Article] Enhanced glycolysis induced by mtDNA mutations does not regulate metastasis (2008)
  • Author(s): Kaori Ishikawa, Osamu Hashizume, Nobuko Koshikawa, Sayaka Fukuda, Kazuto Nakada, Keizo Takenaga, and Jun-Ichi Hayashi
  • Journal Title: FEBS Lett Volume: 582 Pages: 3525-3350
  • URL: https://www.tulips.tsukuba.ac.jp/dspace/handle/2241/101219
  • Peer Reviewed
• [Journal Article] ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis (2008)
  • Author(s): Kaori Ishikawa, Keizo Takenaga, Miho Akimoto, Nobuko Koshikawa, Aya Yamaguchi, Hirotake Imanishi, Kazuto Nakada, Yoshio Honma, and Jun-Ichi Hayashi
  • Journal Title: Science Volume: 320 Pages: 661-664
  • URL: https://www.tulips.tsukuba.ac.jp/dspace/handle/2241/101575
  • Peer Reviewed
• [Journal Article] Pathogenic mitochondrial DNA-induced respiration defects in hematopoietic cells result in anemia by suppressing erythroid differentiation (2007)
  • Author(s): Shin-Ichi Inoue, Mutsumi Yokota, Kazuto Nakada, Hiroyuki Miyoshi, and Jun-Ichi Hayashi
  • Journal Title: FEBS Lett Volume: 581 Pages: 1910-1906
  • Peer Reviewed
• [Journal Article] The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells (2007)
  • Author(s): Liqin Cao, Hiroshi Shitara, Takuro Horii, Yasumitsu Nagao, Hiroshi Imai, Kuniya Abe, Takahiko Hara, Jun-Ichi Hayashi, and Hiromichi Yonekawa
  • Journal Title: Nat. Genet Volume: 39 Pages: 386-390
  • Peer Reviewed
• [Journal Article] Deletion-mutant mtDNA increases in somatic tissues but decreases in female germ cells with age (2007)
  • Author(s): Akitsugu Sato, Kazuto Nakada, Hiroshi Shitara, Atsuko Kasahara, Hitomichi Yonekawa, and Jun-Ichi Hayashi
  • Journal Title: Geneics Volume: 177 Pages: 2031-2037
  • Peer Reviewed
• [Presentation] 特別講演:ミトコンドリアDNA突然変異とがん転移能 (2009)
  • Author(s): 林純一
  • Organizer: 第28回分子病理学研究会
  • Place of Presentation: 神戸
  • Year and Date: 2009-07-19
• [Presentation] Symposium : Mitochondrial genome and cellular functions : Mitochondrial bottleneck is not generated by the reduction of mtDNA copy number in mouse female germlines (2008)
  • Author(s): Jun-Ichi Hayashi
  • Organizer: 第31回日本分子生物学会年会、第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-12
• [Presentation] From basic mechanisms to disease and ageing-Role of mtDNA mutations in metastasis City Conference Centre (2008)
  • Author(s): Jun-Ichi Hayashi
  • Organizer: The 7th European meeting on mitochondrial pathology (EUROMIT VII)
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2008-06-13
• [Book] 細胞工学 (2010)
  • Author(s): 今西泰赳, 石川香, 反町典子, 林純一
  • Total Pages: 416-417
  • Publisher: 学研メディカル秀潤社
• [Book] Methods in Enzymology, Part B, Mitochondrial function (Edited by W. S. Allison and Anne N. Murphy), Generation of mtDNA-exchanged cybrids for determination of the effects of mtDNA mutations on tumor phenotypes (2009)
  • Author(s): Kaori Ishikawa, Jun-Ichi Hayashi
  • Total Pages: 335-346
  • Publisher: Academic Press
• [Remarks] 研究室ホームページ
  • URL: http://www.biol.tsukuba.ac.jp/~jih-kzt/
• [Remarks] 筑波大学公式HP(プレス用記事)
  • URL: http://www.tsukuba.ac.jp/public/press/080402press_mitocondoria.pdf
• [Remarks] 日本学術振興会最近の研究成果
  • URL: http://www.jsps.go.jp/j-grantsinaid/31_result/seibutsu/23_hayashi.html