Cooperative regulation of mitochondrial membrane and genome in mammalian cells

• Project/Area Number: 17H03677
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cell biology
• Research Institution: Osaka University
• Principal Investigator: ISHIHARA Naotada 大阪大学, 理学研究科, 教授 (10325516)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: ミトコンドリア / オルガネラ / 生体膜 / 膜融合 / 膜分裂 / 酸素呼吸 / ミトコンドリアDNA / GTPase / mtDNA / 蛋白質 / 遺伝子 / 細胞・組織 / 膜構造

Outline of Final Research Achievements

It was well known that mitochondria are highly dynamic organelle by mitochondrial movement and the active membrane fusion and fission. Here we analyzed molecular mechanism of dynamic regulation of mitochondrial morphology, and found that the mitochondrial membrane and mitochondrial DNA are cooperatively regulated under dynamic membrane fusion and fission to modulate mitochondrial respiratory activity in cultured mammalian cells.

Academic Significance and Societal Importance of the Research Achievements

ミトコンドリアは2重膜構造からなる酸素呼吸に必須の細胞内小器官であり、エネルギー生産のみならず細胞死等の様々な細胞制御に関与している。ミトコンドリアの融合と分裂による動的な形態変化は、哺乳動物の全身レベルでの初期発生・分化、さらには様々な病態や老化などにも関与していることが明らかになりつつある。今回の基礎的な研究から見出されたミトコンドリアの新規の分子情報は、個体の恒常性維持や病態・老化等におけるミトコンドリアの役割をより深く理解する基盤的かつ重要な知見を与えるものである。

Research Products

• [Journal Article] Mitochondrial nucleoid morphology and respiratory function are altered in Drp1-deficient HeLa cells (2020)
  • Author(s): Ota Azusa、Ishihara Takaya、Ishihara Naotada
  • Journal Title: The Journal of Biochemistry Volume: 167 Issue: 3 Pages: 287-294
  • DOI: 10.1093/jb/mvz112
  • Peer Reviewed
• [Journal Article] Mitochondrial dynamics and interorganellar communication in the development and dysmorphism of mammalian oocytes (2020)
  • Author(s): Udagawa Osamu、Ishihara Naotada
  • Journal Title: The Journal of Biochemistry Volume: 167 Issue: 3 Pages: 257-266
  • DOI: 10.1093/jb/mvz093
  • Peer Reviewed / Open Access
• [Journal Article] ミトコンドリア構造の動的変化と疾患 (2020)
  • Author(s): 安田 樹、石原 孝也、石原 直忠
  • Journal Title: 遺伝子医学MOOK「ミトコンドリアと病気」 Volume: 35 Pages: 286-290
• [Journal Article] Regulation of mitochondrial inner-membrane fusion by OPA1 and cardiolipin (2019)
  • Author(s): 植田 依里, 伴 匡人, 石原 直忠
  • Journal Title: 生化学 Volume: 91 Issue: 2 Pages: 268-271
  • DOI: 10.14952/SEIKAGAKU.2019.910268
  • NAID: 40021942535
  • ISSN: 0037-1017
  • Year and Date: 2019-04-25
  • Peer Reviewed / Open Access
• [Journal Article] ミトコンドリア膜融合反応の試験管内再構成とその分子解析 (2019)
  • Author(s): 石原 直忠
  • Journal Title: 生産と技術 Volume: 71 Pages: 74-76
  • NAID: 40021969881
  • Open Access
• [Journal Article] ミトコンドリア構造のダイナミックな制御機構 (2019)
  • Author(s): 古田 詩唯奈、石原 直忠
  • Journal Title: 実験医学増刊 「ミトコンドリアと疾患・老化」 Volume: 37 Pages: 1890-1895
• [Journal Article] Mitochondrial hyperfusion causes neuropathy in a fly model of CMT2A (2018)
  • Author(s): Ueda Eri、Ishihara Naotada
  • Journal Title: EMBO reports Volume: 19 Issue: 8
  • DOI: 10.15252/embr.201846502
• [Journal Article] Relationship between OPA1 and cardiolipin in mitochondrial inner-membrane fusion (2018)
  • Author(s): Ban Tadato、Kohno Hiroto、Ishihara Takaya、Ishihara Naotada
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Bioenergetics Volume: 1859 Issue: 9 Pages: 951-957
  • DOI: 10.1016/j.bbabio.2018.05.016
  • Peer Reviewed
• [Journal Article] Circadian Control of DRP1 Activity Regulates Mitochondrial Dynamics and Bioenergetics (2018)
  • Author(s): Schmitt Karen、Grimm Amandine、Dallmann Robert、Oettinghaus Bjoern、Restelli Lisa Michelle、Witzig Melissa、Ishihara Naotada、Mihara Katsuyoshi、Ripperger Jurgen A.、Albrecht Urs、Frank Stephan、Brown Steven A.、Eckert Anne
  • Journal Title: Cell Metabolism Volume: 27 Issue: 3 Pages: 657-666.e5
  • DOI: 10.1016/j.cmet.2018.01.011
• [Journal Article] Uncoupled mitochondria quickly shorten along their long axis to form indented spheroids, instead of rings, in a fission-independent manner. (2018)
  • Author(s): Miyazono Yoshihiro, Shingo Hirashima, Naotada Ishihara, Jingo Kusukawa, Kei-ichiro Nakamura, and Keisuke Ohta
  • Journal Title: Scientific Report Volume: 8 Issue: 1 Pages: 350-350
  • DOI: 10.1038/s41598-017-18582-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PARL paves the way to apoptosis. (2017)
  • Author(s): N. Ishihara and K. Mihara.
  • Journal Title: Nat. Cell Biol. Volume: 19 Issue: 4 Pages: 263-265
  • DOI: 10.1038/ncb3504
  • Int'l Joint Research
• [Journal Article] Three-dimensional analysis of somatic mitochondrial dynamics in fission-deficient injured motor neurons using FIB/SEM (2017)
  • Author(s): Tamada H, Kiryu-Seo S, Hosokawa H, Ohta K, Ishihara N, Nomura M, Mihara K, Nakamura KI, Kiyama H
  • Journal Title: Jounral of Comparative Neurology Volume: 印刷中 Issue: 11 Pages: 1-14
  • DOI: 10.1002/cne.24213
  • NAID: 120006343671
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Aclarubicin, an anthracycline anti-cancer drug, fluorescently contrasts mitochondria and reduces the oxygen consumption rate in living human cells (2017)
  • Author(s): Iihoshi Haruka、Ishihara Takaya、Kuroda Shogo、Ishihara Naotada、Saitoh Hisato
  • Journal Title: Toxicology Letters Volume: 277 Pages: 109-114
  • DOI: 10.1016/j.toxlet.2017.06.006
  • Peer Reviewed
• [Journal Article] Cell-free mitochondrial fusion assay detected by specificprotease reaction revealed Ca2+ as regulator of mitofusin dependent mitochondrial fusion (2017)
  • Author(s): Ishihara N, Maeda M, Ban T, Mihara K.
  • Journal Title: J Biochem Volume: 印刷中 Pages: 287-294
  • DOI: 10.1093/jb/mvx029
  • Peer Reviewed
• [Journal Article] Expression and purification of recombinant human L-OPA1 using BmNPV bacmid-silkworm expression system (2017)
  • Author(s): Ban Tadato、Ishihara Naotada
  • Journal Title: Protocol Exchange Volume: -
  • DOI: 10.1038/protex.2017.053
  • Open Access
• [Journal Article] D-Glutamate is metabolized in the heart mitochondria. (2016)
  • Author(s): M. Ariyoshi, M. Katane, K. Hamase, Y. Miyoshi, M. Nakane, A. Hoshino, Y. Okawa, Y. Mita, S. Kaimoto, M. Uchihashi, K. Fukai, K. Ono, S. Tateishi, D. Hato, R. Yamanaka, S. Honda, Y. Fushimura, E. Iwai-Kanai, N. Ishihara, M. Mita, H. Homma, and S. Matoba.
  • Journal Title: Sci. Rep. Volume: 7 Issue: 1 Pages: 43911-43911
  • DOI: 10.1038/srep43911
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Roles of mitochondrial dynamics in cellular function, development, and differentiation (2019)
  • Author(s): Ishihara Naotada, Ishihara Takaya, Ogasawara Emi, Ban Tadato.
  • Organizer: FAOAP 2019
  • Int'l Joint Research / Invited
• [Presentation] ミトコンドリアにおける核様体の動態を制御する新規因子の同定 (2019)
  • Author(s): 古田 詩唯奈、太田 あずさ、石原 孝也、石原 直忠
  • Organizer: 第71回日本細胞生物学会大会
• [Presentation] ミトコンドリア分裂因子のミトコンドリア抗ウイルス応答における新たな調節機能 (2019)
  • Author(s): 花田 有希、石原 孝也、野村 政壽、小川 佳宏、石原 直忠
  • Organizer: 第19回日本蛋白質科学会年会・第71回日本細胞生物学会大会 合同年次大会
• [Presentation] mtDNAからなる核様体の形態や配置を制御する因子の探索 (2019)
  • Author(s): Ota Azusa, Ishihara Takaya, Ban Tadato, Ishihara Naotada
  • Organizer: 第19回日本蛋白質科学会年会・第71回日本細胞生物学会大会 合同年次大会
• [Presentation] Live imaging of mitochondrial nucleoid fission in living mammalian cells (2019)
  • Author(s): Kanon Hirotaka, Ishihara Takaya, Ishihara Naotada
  • Organizer: 第19回日本蛋白質科学会年会・第71回日本細胞生物学会大会 合同年次大会
• [Presentation] ミトコンドリア膜融合 GTPase OPA1 による膜融合機構の解析 (2019)
  • Author(s): 伴 匡人、石原 直忠
  • Organizer: 第19回日本蛋白質科学会年会・第71回日本細胞生物学会大会 合同年次大会
• [Presentation] 脂質によるミトコンドリア膜の融合制御と品質管理 (2019)
  • Author(s): 石原 直忠
  • Organizer: 第61 回 日本脂質生化学会
  • Invited
• [Presentation] 哺乳動物のミトコンドリア構造の動的変化による生命機能制御 (2019)
  • Author(s): 石原 直忠
  • Organizer: 第136回日本育種学会
  • Invited
• [Presentation] Dynamic regulation of mitochondrial double membranes and genome (2019)
  • Author(s): Ishihara Naotada, Ishihara Takaya, Ogasawara Emi, Ban Tadato.
  • Organizer: 第92回日本生化学会年会
  • Invited
• [Presentation] Elucidating molecular mechanism of mitochondrial inner membrane fusion using reconstitution experiment. (2019)
  • Author(s): Ban Tadato, Ishihara Naotada
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] Dynamic regulation and pathogenicity of mutated mitochondrial DNA in mammals (2019)
  • Author(s): Ogasawara Emi, Nakada Kazuto, Ishihara Naotada.
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] ミトコンドリアのダイナミックな形態制御とその個体における意義 (2019)
  • Author(s): 小笠原 絵美、石原 孝也、伴 匡人、石原 直忠
  • Organizer: 第51回日本臨床分子形態学会総会・学術集会
  • Invited
• [Presentation] Regulation of pathogenicity of dynamics of mutated mitochondrial DNA heteroplasmy (2019)
  • Author(s): Ogasawara Emi, Nakada Kazuto, Ishihara Naotada.
  • Organizer: The 16th Conference of Asia Society for Mitochondrial Research and Medicine [ASMRM] & The 19th Conference of Japanese Society of Mitochondrial Research and Medicine [J-Mit],
  • Int'l Joint Research
• [Presentation] Analysis of mitochondrial outer membrane fusion by Fzo. (2019)
  • Author(s): Marui Takuma, Ueda Eri, Ban Tadato, Ishihara Naotada.
  • Organizer: The 16th Conference of Asia Society for Mitochondrial Research and Medicine [ASMRM] & The 19th Conference of Japanese Society of Mitochondrial Research and Medicine [J-Mit],
  • Int'l Joint Research
• [Presentation] Regulation and dynamics of intramitochondrial structures (2019)
  • Author(s): Ishihara Naotada, Ishihara Takaya, Ogasawara Emi, Ban Tadato.
  • Organizer: The 16th Conference of Asia Society for Mitochondrial Research and Medicine [ASMRM] & The 19th Conference of Japanese Society of Mitochondrial Research and Medicine [J-Mit]
  • Int'l Joint Research / Invited
• [Presentation] Dynamic regulation of mitochondrial double membranes and genome (2019)
  • Author(s): Azusa Ota, Yuki Hanada, Emi Ogasawara, Takaya Ishihara, Tadato Ban, and Naotada Ishihara
  • Organizer: Cold spring haever asia, 2019, Mitochondria and Metabolism in Health and Disease
  • Int'l Joint Research / Invited
• [Presentation] Regulation of pathogenicity by dynamics of mutated mitochondrial DNA. (2019)
  • Author(s): Ogasawara Emi, Nakada Kazuto, Ishihara Nnaotada
  • Organizer: Cold spring haever asia, 2019, Mitochondria and Metabolism in Health and Disease
  • Int'l Joint Research
• [Presentation] Live imaging of mitochondrial nucleoid fission in living mammalian cells. (2019)
  • Author(s): Kanon Hirotaka, Ishihara Takaya, Ishihara Naotada.
  • Organizer: Cold spring haever asia, 2019, Mitochondria and Metabolism in Health and Disease
  • Int'l Joint Research
• [Presentation] Selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin (2018)
  • Author(s): Tadato Ban, and Naotada Ishihara
  • Organizer: Keystone symposia, Mitochondrial Biology
  • Int'l Joint Research
• [Presentation] ミトコンドリアの融合・分裂の制御とその生理的意義 (2018)
  • Author(s): 石原直忠
  • Organizer: 第55回日本臨床分子医学会
  • Invited
• [Presentation] Dynamics of mitochondrial membranes and genome for mitochondrial quality control (2018)
  • Author(s): Naotada Ishihara
  • Organizer: 細胞生物学会・発生生物学会 合同学会
  • Invited
• [Presentation] 卵子形成におけるミトコンドリアのダイナミックな構造変化 (2018)
  • Author(s): 石原直忠
  • Organizer: 第36回日本受精着床学会
  • Invited
• [Presentation] Dynamics of mitochondrial double membranes, genomes, and functions. (2018)
  • Author(s): N. Ishihara
  • Organizer: 20th European Bioenergetics Conference (EBEC2018)
  • Int'l Joint Research / Invited
• [Presentation] Roles of mitochondrial dynamics in development and differentiation. (2018)
  • Author(s): N. Ishihara
  • Organizer: Japan-Korea-China Young Researchers; Symposium “Organelle dynamics in Reproductive Biology”
  • Int'l Joint Research / Invited
• [Presentation] Dynamic regulation of mitochondrial double membranes and genome (2018)
  • Author(s): N.Ishihara
  • Organizer: Asian Society of Mitochondrial Research and Medicine (ASMRM 2018)
  • Int'l Joint Research / Invited
• [Presentation] ミトコンドリアの融合・分裂の制御とその生理的意義 （シンポジウム） (2017)
  • Author(s): 石原直忠、伴匡人、石原孝也、太田あずさ、一村紋佳
  • Organizer: 第17回日本ミトコンドリア学会年会
  • Invited
• [Presentation] ミトコンドリアの膜とゲノムのダイナミックな形態制御とその意義（シンポジウム） (2017)
  • Author(s): 伴匡人、石原孝也、太田あずさ、一村紋佳、石原直忠
  • Organizer: 2017年度生命科学系学会合同年次大会(ConBio2017)
  • Invited
• [Presentation] Roles of mitochondrial dynamics in cellular function, development, and differentiation. （シンポジウム） (2017)
  • Author(s): Naotada Ishihara
  • Organizer: Cardiovascular and Metabolic Week 2017 (CVMW 2017)
  • Invited
• [Presentation] ミトコンドリアの2重膜構造の動的変化によるミトコンドリア機能の制御（招待講演） (2017)
  • Author(s): 伴匡人、石原孝也、太田あずさ、石原直忠
  • Organizer: 日本生体エネルギー研究会第43回討論会
• [Remarks]
  • URL: https://www.bio.sci.osaka-u.ac.jp/dbs01/re-paper-temp.php?id=100
• [Remarks] 大阪大学大学院 理学研究科生物科学専攻
  • URL: https://www.bio.sci.osaka-u.ac.jp/dbs01/re-paper-temp.php?id=100
• [Remarks] ミトコンドリア研究 石原研究室
  • URL: http://mitochondria.jp/