Role of MITOL in mitochondrial dynamics

• Project/Area Number: 26293072
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: YANAGI Shigeru 東京薬科大学, 生命科学部, 教授 (60252003)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: ミトコンドリア / ユビキチンリガーゼ / 小胞体ストレス / MAM

Outline of Final Research Achievements

Previously, we identified the mitochondrial ubiquitin ligase MITOL and demonstrated that MITOL mediates lysine-63-linked polyubiquitin chain addition to Mfn2 and induces the mitochondria-associated ER membrane (MAM) formation through Mfn2 oligomerization. However, the physiological roles of MITOL in MAM structure and function in vivo remain unknown. In this study, I obserbed the MAM structure in MITOL-KO brain using 3D-SEM analysis, and found that MITOL regulates mitochondrial morphology and cardiolipin biogenesis through Mfn2-dependent MAM formation in vivo. Furthermore, we found that MITOL inhibits ER stress-induced apoptosis by IRE1α ubiquitylation at the MAM. MITOL adds lysine (K) 63-linked polyubiquitin chain to K481 of IRE1α, thereby preventing hyper-oligomerization of IRE1α and regulated IRE1α-dependent decay of mRNA activity. Our findings provide a novel concept that mitochondria determine cell fate under ER stress through IRE1α regulation by MITOL at the MAM.

Research Products

• [Journal Article] 小胞体-ミトコンドリア接触場の形成制御とアルツハイマー病 (2016)
  • Author(s): 武田啓佑、柳 茂
  • Journal Title: 医学のあゆみ Volume: 26020 Pages: 24-30
• [Journal Article] Rescue of CAMDI deletion-induced delayed radial migration and psychiatric behaviors by HDAC6 inhibitor. (2016)
  • Author(s): Fukuda, T., Nagashima, S., Abe, T., Kiyonari, H., Inatome, R. and Yanagi, S.
  • Journal Title: EMBO. Rep. Volume: 17 Issue: 12 Pages: 1785-1798
  • DOI: 10.15252/embr.201642416
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of B cell differentiation by the ubiquitin-binding protein TAX1BP1. (2016)
  • Author(s): Matsushita, N., Suzuki, M., Ikebe, E., Nagashima, S., Inatome, R., Asano, K., Tanaka, M., Matsushita, M., Kondo, E., Iha, H., and Yanagi, S.
  • Journal Title: Sci. Rep. Volume: 63 Pages: 31266-31266
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sox11 balances dendritic morphogenesis with neuronal migration in the developing cerebral cortex. (2016)
  • Author(s): 1.Hoshibam, Y., Toda, T., Ebisu, H., Wakimoto, M., Yanagi, E., and Kawasaki, H.
  • Journal Title: J. Neurosci. Volume: in press
  • NAID: 120005830579
  • Peer Reviewed
• [Journal Article] Roles of mitochondrial ubiquitin ligase MITOL/MARCH5 in mitochondrial dynamics and diseases (2014)
  • Author(s): Nagashima, S., Tokuyama, T., Yonashiro, R., Inatome, R., and Yanagi S.
  • Journal Title: J. Biochem Volume: 155 Issue: 5 Pages: 273-279
  • DOI: 10.1093/jb/mvu016
  • Peer Reviewed
• [Journal Article] One-year follow-up of gene expression by integrase-defective lentiviral vectors and their therapeutic potential in spinocerebellar ataxia model mice. (2014)
  • Author(s): Saida H, Matsuzaki Y, Takayama K, Iizuka A, Konno A, Yanagi S, and Hirai H.
  • Journal Title: Gene Therapy Volume: 21 Issue: 9 Pages: 820-827
  • DOI: 10.1038/gt.2014.60
  • Peer Reviewed
• [Journal Article] Downregulation of Centaurin gamma1A increases synaptic transmission at Drosophila larval neuromuscular junctions (2014)
  • Author(s): Homma, M.、 Nagashima, S., Fukuda, T., Yanagi, S., Miyakawa, H., Suzuki, E., Morimoto, T.
  • Journal Title: Europian Journal of Neuroscience Volume: VOL40 Issue: 8 Pages: 3158-3170
  • DOI: 10.1111/ejn.12681
  • Peer Reviewed
• [Presentation] ミトコンドリアユビキチンリガーゼMITOLによるミトコンドリア品質管理機構 (2016)
  • Author(s): 柳 茂
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-11
  • Invited
• [Presentation] ミトコンドリアユビキチンリガーゼMITOLによるMAM制御機構と破綻による疾患 (2014)
  • Author(s): 柳 茂、徳山剛士、武田啓祐、稲留涼子、長島 駿
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15