Elucidation of organelle network mechanism controlled by mitochondrial dynamics and its application.

• Project/Area Number: 26461383
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Kyushu University
• Principal Investigator: Nomura Masatoshi 九州大学, 大学病院, 講師 (30315080)
• Co-Investigator(Renkei-kenkyūsha): ISHIHARA Naotada 久留米大学, 分子生命科学, 教授 (10325516) ; YAMADA Yuma 北海道大学, 薬学研究院, 助教 (60451431)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ミトコンドリア / 糖尿病 / 小胞体ストレス / DRP1 / DRP１ / ミトコンドリアダイナミクス / Drp1 / Mff / 糖代謝 / メタボリックシンドローム / オルガネラネットワーク / FGF21 / 肥満

Outline of Final Research Achievements

Mitochondria are highly dynamic organelles that frequently fuse and divide in response to cellular energy demands. In an excessive energy state such as a high fat diet, the organelle network between Mt and ER is impaired, followed by the induction of ER stress. As a result, FGF21 is secreted from the liver by activation of PERK-eIF2a-ATF4 pathway, and energy expenditure is accelerated in the peripheral organs such as skeletal muscle and adipose tissue. In other words, mitochondrial dynamics-ER stress-FGF21 axis function as a biological defense system for energy excess. Therefore, mitochondrial dynamics is a therapeutic target for the obese diabetes.

Research Products

• [Int'l Joint Research] Columbia University/Harvard Medical School(米国)
• [Journal Article] Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure. (2016)
  • Author(s): Akihiro Shirakabe, Peiyong Zhai, Yoshiyuki Ikeda, Toshiro Saito, Yasuhiro Maejima, Chiao-Po Hsu, Masatoshi Nomura, Kensuke Egashira, Beth Levine, Junichi Sadoshima,
  • Journal Title: Circulation Volume: 133 Issue: 13 Pages: 1249-1263
  • DOI: 10.1161/circulationaha.115.020502
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Smad2/3 Proteins Are Required for Immobilization-induced Skeletal Muscle Atrophy (2016)
  • Author(s): Tando T, Hirayama A, Furukawa M, Sato Y, Kobayashi T, Funayama A, Kanaji A, Hao W, Watanabe R, Morita M, Oike T, Miyamoto K, Soga T, Nomura M, Yoshimura A, Tomita M, Matsumoto M, Nakamura M, Toyama Y, Miyamoto T
  • Journal Title: J Biol Chem Volume: 291 Issue: 23 Pages: 12184-94
  • DOI: 10.1074/jbc.m115.680579
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Distinct types of protease systems are involved in homeostasis regulation of mitochondrial morphology via balanced fusion and fission. (2016)
  • Author(s): S. Saita, T. Ishihara, M.Maeda, S. Iemura, T. Natsume, K. Mihara and N. Ishihara.
  • Journal Title: Genes Cells. Volume: 21 Issue: 1 Pages: 408-424
  • DOI: 10.1038/srep28331
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Urothelial ATP exocytosis: regulation of bladder compliance in the urine storage phase (2016)
  • Author(s): Nakagomi H,Yoshiyama M,Mochizuki T,Miyamoto T,Komatsu R,Imura Y,Morizawa Y,Hiasa M,Kira S,Fujishita K,Shibata K,Shigetomi E,Shinozaki Y,Takeda M,Koizumi S
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 29761-29761
  • DOI: 10.1038/srep29761
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] BubR1 Insufficiency Impairs Liver Regeneration in Aged Mice after Hepatectomy through Intercalated Disc Abnormality (2016)
  • Author(s): A. Ikawa-Yoshida, T. Matsumoto, S. Okano, Y. Aoyagi, Y. Matsubara, T. Furuyama, Y. Nakatsu, T. Tsuzuki, M. Onimaru, T. Ohkusa, M. Nomura, Y. Maehara,
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 32399-32399
  • DOI: 10.1038/srep32399
  • Peer Reviewed / Open Access
• [Journal Article] Dehydroepiandrosterone-enhanced dual specificity protein phosphatase (DDSP) prevents diet-induced and genetic obesity. (2015)
  • Author(s): Watanabe T, Ashida K, Goto K, Nawata H, Takayanagi R, Yanase T, Nomura M
  • Journal Title: Biochem Biophys Res Commun Volume: 468 Issue: 1-2 Pages: 196-201
  • DOI: 10.1016/j.bbrc.2015.10.131
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of Drp1 in the liver leads to an alteration in expression of the genes involved in the immune system. (2015)
  • Author(s): Wang L, Nomura M
  • Journal Title: Genomic Data Volume: 6 Pages: 27-30
  • DOI: 10.1016/j.gdata.2015.07.021
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration. (2015)
  • Author(s): Wang L, Ishihara T, Ibayashi Y, Tatsushima K, Setoyama D, Hanada Y, Takeichi Y, Sakamoto S, Yokota S, Mihara K, Kang D, Ishihara N, Takayanagi R, Nomura M
  • Journal Title: Diabetologia Volume: 58 Issue: 10 Pages: 2371-2380
  • DOI: 10.1007/s00125-015-3704-7
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Smad2 and Smad3 inversely regulate TGF-β autoinduction in Clostridium butyricum-activated dendritic cells. (2015)
  • Author(s): Kashiwagi K, Morita R, Schichita T, Komai K, Saeki K, Matsumoto M, Takeda K, Nomura M, Hayashi A, Kanai T, Yoshimura A
  • Journal Title: Immunity Volume: 43 Issue: 1 Pages: 65-79
  • DOI: 10.1016/j.immuni.2015.06.010
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Dietary vitamin D3 improves postprandial hyperglycemia in aged mice. (2015)
  • Author(s): Enciso P, Wang L, Kawahara Y, Sakamoto S, Shimada S, Takeichi Y, Takayanagi R, Nomura M
  • Journal Title: Biochem Biophys Res Commun Volume: 461 Issue: 1 Pages: 165-171
  • DOI: 10.1016/j.bbrc.2015.04.008
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Dynamics of mtDNA nucleoids regulated by mitochondrial fission is essential for maintenance of homogeneously active mitochondria during neonatal heart development. (2015)
  • Author(s): T. Ishihara, R. Ban-Ishihara, M. Maeda, Y. Matsunaga, A. Ichimura, S. Kyogoku, H. Aoki, S. Katadam K. Nakada, M. Nomura, N. Mizushima, K. Mihara, and N. Ishihara
  • Journal Title: Molecular Cell Biology Volume: 35 Issue: 1 Pages: 211-223
  • DOI: 10.1128/mcb.01054-14
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Endogenous Drp1 Mediates Mitochondrial Autophagy and Protects the Heart Agains Energy Stress. (2015)
  • Author(s): Y. Ikeda, A. Shitakabe, Y. Maejeima, P. Zhai, S. Sciarretta, J. Toli, M. Nomura, K.Mihara, K. Egashira, M. Ohnishi, M. Abdellatif and J. Sadoshima
  • Journal Title: Circulation Research Volume: 116 Issue: 2 Pages: 264-278
  • DOI: 10.1161/circresaha.116.303356
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SMAD2 disruption in meuse pancreatic beta cells leads to islet hyperplasia and impaired insulin secretion due to the attenuation of ATP-sengitive K+ channel activity. (2014)
  • Author(s): Nomura M, Zhu HL, Wang L, Morinaga H, Takayanagi R, Teramoto N.
  • Journal Title: Diabetologia Volume: 57 Issue: 1 Pages: 157-166
  • DOI: 10.1007/s00125-013-3062-2
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive behavioral study of mGluR3 knockout mice: implication in schizophrenia related endophenotypes. (2014)
  • Author(s): Fujioka R, Nii T, Iwaki A, Shibata A, Ito I, Kitaichi K, Nomura M, Hattori S, Takao K, Miyakawa T, Fukumaki Y.
  • Journal Title: Mol Brain Volume: 7 Issue: 1 Pages: 31-31
  • DOI: 10.1186/1756-6606-7-31
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Microglia trigger astrocyte-mediated neuroprotection via purinergic gliotransmission (2014)
  • Author(s): Y. Shinozaki., M. Nomura., K. Iwatsuki., Y. Moriyama., C. Gachet., S. Koizumi.
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 4329-4329
  • DOI: 10.1038/srep04329
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A nanocarrier system for the delivery of nucleic acids targeted to a pancreatic beta cell line (2014)
  • Author(s): Yamada Y., Tabata M., Yasuzaki Y., Nomura M., Shibata A., Ibayashi Y., Taniguchi Y., Sasaki S., Harashima H.
  • Journal Title: Biomaterials Volume: 35 Issue: 24 Pages: 6430-6438
  • DOI: 10.1016/j.biomaterials.2014.04.017
  • NAID: 120005512023
  • Peer Reviewed
• [Journal Article] Overexpression of constitutive active form of ActRIB in pancreas beta cells leads to impaired insulin secretion in mice. (2014)
  • Author(s): Nomura M, Morinaga H, Hei-lay Z, Wang L, Hasuzawa N, Takayanagi R, Teramoto N
  • Journal Title: Biochem Biophys Res Commun Volume: 450 Issue: 1 Pages: 440-446
  • DOI: 10.1016/j.bbrc.2014.05.141
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mitochondrial Fission Factor Drp1 Maintains Oocyte Quality via Dynamic Rearrangement of Multiple Organelles (2014)
  • Author(s): O Udagawa, T Ishihara, M Maeda, Y Matsunaga, S Tsukamoto, N Kawano, K Miyado, H Shitara, S Yokota, M Nomura, K Mihara, N Mizushima, N Ishihara
  • Journal Title: Current Biology Volume: 24 Issue: 20 Pages: 2451-2458
  • DOI: 10.1016/j.cub.2014.08.060
  • Peer Reviewed / Open Access
• [Journal Article] Impairment of vesicular ATP release affects glucose metabolism and increases insulin sensitivity (2014)
  • Author(s): Sakamoto S., Miyaji T.,, Hiasa M., Ichikawa R., Iwatsuki K., Shibata A., Uneyama H., Takayanagi R., Yamamoto A., Omote H., Nomura M., Moriyama Y.
  • Journal Title: Sci. Rep. Volume: 4 Issue: 1 Pages: 6689-6689
  • DOI: 10.1038/srep06689
  • Peer Reviewed / Open Access
• [Presentation] mpact of mitochondrial dynamics on metabolic disease and inflammation (2016)
  • Author(s): Lixiang Wang, Yuki Hanada, Yuta Ibayashi, Yukina Takeichi, Shohei Sakamoto, Kenji Ashida, Masatoshi Nomura
  • Organizer: Targeting Mitochondria Wourld Congress
  • Place of Presentation: Hotel Maritim ProArte, Berlin
  • Year and Date: 2016-10-24
  • Int'l Joint Research
• [Presentation] Mitochondrial fission role in brown adipose tissue (2016)
  • Author(s): Yuta Ibayashi, Lixiang Wang, Yuki Hanada, Yukina Takeichi, Shohei Sakamoto, Kenji Ashida, Masatoshi Nomura
  • Organizer: Targeting Mitochondria Wourld Congress
  • Place of Presentation: Hotel Maritim ProArte, Berlin
  • Year and Date: 2016-10-24
• [Presentation] ミトコンドリア分裂の炎症における役割 (2016)
  • Author(s): 王麗香 井林雄太 武市幸奈 花田有希 坂本昌平 蘆田健二 野村政壽
  • Organizer: 第89回日本内分泌学会学術総会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-04-21
• [Presentation] ミトコンドリア分裂因子（Mff）は飽和脂肪酸により惹起される炎症を制御する (2016)
  • Author(s): 花田有希, 王麗香, 武市幸奈, 嶋田伸吾, 坂本昌平, 蘆田健二, 野村政壽
  • Organizer: 第89回日本内分泌学会学術総会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-04-21
• [Presentation] 脂肪細胞特異的Drp1遺伝子欠損マウスの表現型解析 (2015)
  • Author(s): 井林雄太、王麗香、野村政壽、他
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: ホテルニューオータニ東京
  • Year and Date: 2015-04-23
• [Presentation] Mitochondrial fission factor (Mff)遺伝子欠損マウスの表現型解析 (2015)
  • Author(s): 嶋田伸吾、王麗華、武市幸奈、大寺秀典、高栁涼一、三原勝芳、野村政壽
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: ホテルニューオータニ東京
  • Year and Date: 2015-04-23
• [Presentation] 肝Drp1欠損はFgf21を誘導することでエネルギー代謝を亢進させ、食餌性肥満を改善する (2015)
  • Author(s): 王麗香、野村政壽、他
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: ホテルニューオータニ東京
  • Year and Date: 2015-04-23
• [Presentation] 膵β細胞を標的とした核酸送達キャリアの構築およびin vivoへの応用 (2014)
  • Author(s): 田端麻衣, 山田勇磨、野村政壽、原島秀吉
  • Organizer: 第36回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 徳島大学
  • Year and Date: 2014-11-20 – 2014-11-21
• [Presentation] ミトコンドリアダイナミクスを介したエネルギー代謝調節機構 (2014)
  • Author(s): 野村政壽
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26
• [Remarks] 九州大学大学院医学研究院 病態制御内科第一研究室
  • URL: http://www.intmed3.med.kyushu-u.ac.jp/general_1.html