A study to elucidate the role of VAMP7 in mitochondrial quality control in beta-cells and in pathogenesis of type 2 diabetes

• Project/Area Number: 17K09845
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kyorin University
• Principal Investigator: Aoyagi Kyota 杏林大学, 医学部, 講師 (50453527)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: VAMP7 / オートファジー / ミトコンドリア / 膵β細胞 / インスリン分泌 / 糖尿病

Outline of Final Research Achievements

Previously, I reported that VAMP7, a member of SNARE proteins that mediate membrane fusions, is involved in autophagosome formation and degradation of dysfunctional mitochondria in pancreatic beta-cells. However, the role of VAMP7 in autophagosome formation was unclear. In this study, I found that VAMP7 regulates autophagosome formation by supporting Atg9a, a protein essential for autophagosome formation. I also found that mitophagy (selective degradation of mitochondria by autophagy) was facilitated in pancreatic beta-cells of diabetic model mice, suggesting a possibility that maintenance of mitochndrial homeostasis by mitophagy would play a critical role in pathogenesis of type 2 diabetes mellitus.

Academic Significance and Societal Importance of the Research Achievements

以前の研究により、VAMP7遺伝子欠失マウスの膵β細胞には機能不全となったミトコンドリアが蓄積しており、また同マウスを高脂肪食飼育すると耐糖能が悪化し、糖尿病状態となることが明らかになっていた。しかしながらVAMP7がオートファゴソーム形成に関与する分子機構は明らかではなかった。本研究によってオートファゴソーム形成におけるVAMP7の役割が明らかになったことは、VAMP7を標的として機能不全となったミトコンドリアの分解を促進することにより２型糖尿病の発症を抑制する新規治療法の開発につながるものと期待される。

Research Products

• [Journal Article] ELKS/Voltage-dependent Ca2+ channel-β Subunit Module Regulates Polarized Ca2+ Influx in Pancreatic β-Cells. (2019)
  • Author(s): Ohara-Imaizumi, M., Aoyagi, K., Yamauchi, H., Yoshida, M., Mori, M.X., Hida, Y., Tran, H.N., Ohkura, M., Abe, M., Akimoto, Y., Nakamichi, Y., Nishiwaki, C., Kawakami, H., Hara, K., Sakimura, K., Nagamatsu, S., Mori, Y., Nakai, J., Kakei, M., and Ohtsuka, T.
  • Journal Title: Cell Reports Volume: 26 Issue: 5 Pages: 1213-1226
  • DOI: 10.1016/j.celrep.2018.12.106
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of the active zone protein, ELKS, in insulin secretion from pancreatic β-cells (2019)
  • Author(s): Ohara-Imaizumi Mica、Aoyagi Kyota、Ohtsuka Toshihisa
  • Journal Title: Molecular Metabolism Volume: 27 Pages: 1213-1226
  • DOI: 10.1016/j.molmet.2019.06.017
  • Peer Reviewed / Open Access
• [Journal Article] VAMP7 Regulates Autophagosome Formation by Supporting Atg9a Functions in Pancreatic β-Cells From Male Mice (2018)
  • Author(s): Aoyagi Kyota、Itakura Makoto、Fukutomi Toshiyuki、Nishiwaki Chiyono、Nakamichi Yoko、Torii Seiji、Makiyama Tomohiko、Harada Akihiro、Ohara-Imaizumi Mica
  • Journal Title: Endocrinology Volume: 159 Issue: 11 Pages: 3674-3688
  • DOI: 10.1210/en.2018-00447
  • Peer Reviewed / Open Access
• [Journal Article] In vivo regulation of glycogen synthase kinase 3β activity in neurons and brains. (2017)
  • Author(s): Krishnankutty, A., Kimura, T., Saito, T., Aoyagi, K., Asada, A., Takahashi, S., Ando, K., Ohara-Imaizumi, M., Ishiguro, K., Hisanaga, S.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 8602-8602
  • DOI: 10.1038/s41598-017-09239-5
  • Peer Reviewed / Open Access
• [Presentation] VAMP7 regulates autophagosome formation by supporting Atg9a function in pancreatic beta-cells (2019)
  • Author(s): 青柳共太、板倉誠、牧山智彦、西脇知世乃、中道洋子、今泉美佳
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] VAMP7 regulates autophagosome formation by supporting Atg9a functions in pancreatic beta-cells. (2018)
  • Author(s): 青柳共太、板倉誠、福冨俊之、西脇知世乃、中道洋子、鳥居征司、牧山智彦、原田彰宏、今泉美佳
  • Organizer: 第91回日本生化学会大会
• [Presentation] VAMP7 regulates autophagy to maintain mitochondrial homeostasis and to control insulin secretion in pancreatic β-cells (2017)
  • Author(s): Kyota Aoyagi
  • Organizer: 第60回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] 膵β細胞におけるVAMP7によるオートファゴソーム形成の制御機構 (2017)
  • Author(s): 青柳共太、西脇知世乃、中道洋子、福冨俊之、鳥居征司、牧山智彦、櫻井裕之、板倉誠、今泉美佳
  • Organizer: 2017年度生命科学系学会合同年次大会