Post-translational modifications of a mitochondria-resident protein and its role in systemic regulation

• Project/Area Number: 16K15115
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: ICHIJO Hidenori 東京大学, 大学院薬学系研究科(薬学部), 教授 (00242206)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ミトコンドリア / PGAM5 / 翻訳後修飾 / 代謝制御 / 褐色脂肪 / 細胞死

Outline of Final Research Achievements

Mitochondria is indispensable for energy metabolism within the cell, which is also essential for whole-body energy metabolism. PGAM5, a mitochondria-resident protein, has newly clarified as a metabolism regulator in brown adipocytes. PGAM5 somehow senses environmental stresses and conveys signals into the nucleus resulting in the alteration of transcriptome, which includes the suppression of several thermogenic genes. We hereby discovered a novel mechanism that a mitochondria-resident protein regulates mitochondrial energy metabolism through the gene expression regulation in the nucleus.

Research Products

• [Journal Article] ASK family kinases mediate cellular stress and redox signaling to circadian clock (2018)
  • Author(s): Imamura Kiyomichi、Yoshitane Hikari、Hattori Kazuki、Yamaguchi Mitsuo、Yoshida Kento、Okubo Takenori、Naguro Isao、Ichijo Hidenori、Fukada Yoshitaka
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 14 Pages: 3646-3651
  • DOI: 10.1073/pnas.1719298115
  • Peer Reviewed / Open Access
• [Journal Article] A PP6-ASK3 Module Coordinates the Bidirectional Cell Volume Regulation under Osmotic Stress (2018)
  • Author(s): Watanabe Kengo、Umeda Tsuyoshi、Niwa Kuniyoshi、Naguro Isao、Ichijo Hidenori
  • Journal Title: Cell Reports Volume: 22 Issue: 11 Pages: 2809-2817
  • DOI: 10.1016/j.celrep.2018.02.045
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. (2018)
  • Author(s): Galluzzi, L. et al.
  • Journal Title: Cell Death Differ. Volume: 25 Issue: 3 Pages: 486-541
  • DOI: 10.1038/s41418-017-0012-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] mASKing cancer cells in a tumor microenvironment (2018)
  • Author(s): Kamiyama Miki、Naguro, Isao、Ichijo Hidenori
  • Journal Title: Cell Cycle Volume: 17 Issue: 2 Pages: 139-140
  • DOI: 10.1080/15384101.2017.1407402
  • Peer Reviewed / Open Access
• [Journal Article] Apoptosis signal-regulating kinase 1 in regulated necrosis (2018)
  • Author(s): Hattori Kazuki、Ichijo Hidenori
  • Journal Title: Cell Cycle Volume: 17 Issue: 1 Pages: 5-6
  • DOI: 10.1080/15384101.2017.1397330
  • Peer Reviewed / Open Access
• [Journal Article] Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer’s Disease and Brain Aging (2017)
  • Author(s): Hasegawa Yu、Toyama Kensuke、Uekawa Ken、Ichijo Hidenori、Kim-Mitsuyama Shokei
  • Journal Title: Journal of Alzheimer's Disease Volume: 61 Issue: 1 Pages: 259-263
  • DOI: 10.3233/jad-170645
  • Peer Reviewed / Open Access
• [Journal Article] TRIM48 promotes ASK1 activation and cell death through ubiquitination-dependent degradation of the ASK1 negative regulator PRMT1. (2017)
  • Author(s): Hirata, Y., Katagiri, K., Nagaoka, K., Morishita, T., Kudoh, Y., Hatta, T., Naguro, I., Kano, K., Udagawa, T., Natsume, T., Aoki, J., Inada, T., Noguchi, T., Ichijo, H., Matsuzawa, A.
  • Journal Title: Cell Rep. Volume: 21 Issue: 9 Pages: 2447-2457
  • DOI: 10.1016/j.celrep.2017.11.007
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of apoptosis signal-regulating kinase-1 in house dust miteinduced allergic asthma in mice (2017)
  • Author(s): Maruoka, S., Gon, Y., Mizumura, K., Okamoto, S., Tsuya, K., Shikano, S., Soda, K., Naguro, I., Ichijo, H. and Hashimoto, S.
  • Journal Title: Allergology International Volume: 66 Issue: Supplement.1 Pages: S50-S52
  • DOI: 10.1016/j.alit.2017.05.007
  • NAID: 130006182289
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] Cold stress‐induced ferroptosis involves the ASK1‐p38 pathway (2017)
  • Author(s): Hattori Kazuki、Ishikawa Hiroyuki、Sakauchi Chihiro、Takayanagi Saki、Naguro Isao、Ichijo Hidenori
  • Journal Title: EMBO reports Volume: 18 Issue: 11 Pages: 2067-2078
  • DOI: 10.15252/embr.201744228
  • Peer Reviewed / Open Access
• [Journal Article] ASK1 facilitates tumor metastasis through phosphorylation of an ADP receptor P2Y12 in platelets. (2017)
  • Author(s): Kamiyama, M., Shirai, T., Tamura, S., Suzuki-Inoue, K., Ehata, S., Takahashi, K., Miyazono, K., Hayakawa, Y., Sato, T., Takeda, K., Naguro, I., Ichijo, H.
  • Journal Title: Cell Death and Differentiation Volume: 24 Issue: 12 Pages: 2066-2076
  • DOI: 10.1038/cdd.2017.114
  • Peer Reviewed
• [Journal Article] Structures of PGAM5 provide insight into active site plasticity and multimeric assembly. (2017)
  • Author(s): Chaikuad, A., Filippakopoulos, P., Marcsisin, S. R., Picaud, S., Schroder, M., Sekine, S., Ichij, H., Engen, J. R., Takeda, K., Knapp, S.
  • Journal Title: Structure 25, 1089-1099 (2017) Volume: 25 Issue: 7 Pages: 1089-1099
  • DOI: 10.1016/j.str.2017.05.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Apoptosis signal-regulating kinase 1 regulates platelet granule secretion, thromboxane A2 generation, and thrombus formation in mice. (2017)
  • Author(s): Naik, M.-U. Patel, P., Derstine, R., Turaga, R., Chen, X., Golla, K., Neeves, K.-B., Ichijo, H. and Naik, U.-K.
  • Journal Title: Blood Volume: 29 Issue: 9 Pages: 1197-1209
  • DOI: 10.1182/blood-2016-07-729780
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iPSC-based drug repositioning identifies the Src/c-Abl pathway as a therapeutic target for ALS motor neurons. (2017)
  • Author(s): Imamura, K., et al.
  • Journal Title: Sci. Transl. Med. Volume: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pleiotropic properties of ASK1. (2017)
  • Author(s): Sakauchi C, Wakatsuki H, Ichijo H, Hattori K.
  • Journal Title: Biochim Biophys Acta. Volume: 1861 Issue: 1 Pages: 3030-3038
  • DOI: 10.1016/j.bbagen.2016.09.028
  • Peer Reviewed
• [Journal Article] KLHDC10 deficiency protects mice against TNFα-induced systemic inflammation. (2016)
  • Author(s): Yamaguchi, N., Sekine, S., Naguro, I., Sekine, Y. and Ichijo, H.
  • Journal Title: PLOS one Volume: 11 Issue: 9 Pages: e0163118-e0163118
  • DOI: 10.1371/journal.pone.0163118
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction. (2016)
  • Author(s): Koizumi S, Irie T, Hirayama S, Sakurai Y, Yashiroda H, Naguro I, Ichijo H, Hamazaki J, Murata S.
  • Journal Title: Elife Volume: 18357 Pages: 18357-18357
  • DOI: 10.7554/elife.18357
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mitogen-activated protein kinases as key players in osmotic stress signaling. (2016)
  • Author(s): Zhou, X., Naguro, I., Ichijo, H. and Watanabe, K.
  • Journal Title: Biochem. Biophys. Acta Volume: 1860 Issue: 9 Pages: 2037-2052
  • DOI: 10.1016/j.bbagen.2016.05.032
  • Peer Reviewed
• [Journal Article] Mislocalization, aggregation formation and defect in proteolysis in ALS (2016)
  • Author(s): Tsubota, A., Ichijo, H. and Homma, K.
  • Journal Title: AIMS Molecular Science Volume: 3 Issue: 2 Pages: 246-268
  • DOI: 10.3934/molsci.2016.2.246
  • Peer Reviewed
• [Journal Article] ASK1 signaling regulates brown and beige adipocyte maturation (2016)
  • Author(s): Kazuki H, Naguro I, Okabe K, Funatsu T, Furutani S, Takeda K, and Ichijo H
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 11158-11158
  • DOI: 10.1038/ncomms11158
  • Peer Reviewed / Open Access
• [Presentation] Physiological and pathophysiological roles of SOD1 under Zinc deficiency (2017)
  • Author(s): Hidenori Ichijo
  • Organizer: ISZB 5th meeting, in collaboration with Zinc-Net
  • Int'l Joint Research / Invited
• [Presentation] ASK family kinases in Stress Signaling and Disease (2017)
  • Author(s): Hidenori Ichijo
  • Organizer: 58th International Symposium on "Biological Regulation and Enzyme Activity in Normal and Neoplastic Tissues"
  • Int'l Joint Research / Invited
• [Presentation] ストレスシグナルの分子細胞生物学-その破綻と疾患と創薬- (2017)
  • Author(s): 一條秀憲
  • Organizer: 第6回山梨医学フォーラム
  • Invited
• [Presentation] ASK family kinases in Stress Signaling and Disease (2017)
  • Author(s): Hidenori Ichijo
  • Organizer: 第48回高松宮妃癌研究基金国際シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] ミトコンドリア内膜局在型プロテインホスファターゼPGAM5の細胞レベル・個体レベルでの生理機能解析 (2016)
  • Author(s): 菅原祥、服部一輝、一條秀憲
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜、神奈川県横浜市
  • Year and Date: 2016-11-30
• [Book] Advances in BIOLOGICAL REGULATIOＮ (2017)
  • Author(s): Guest Editors: Hidenori Ichijo and Isao Naguro
  • Total Pages: 90
  • Publisher: ELSEVIER