Elucidation of the mechanisms of neutrophil mitochondrial fusion in infection

• Project/Area Number: 18K08423
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Hokkaido University
• Principal Investigator: Mazaki Yuichi 北海道大学, 医学研究院, 講師 (60311304)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 好中球 / ミトコンドリア

Outline of Final Research Achievements

Neutrophils rapidly migrate to infection sites after the recognition of invaders. Previously, we found that mitochondrial morphology changes to a tubular form after fMLP stimulation. In addition, mitochondria oxidative phosphorylation (OXPHOS) activity significantly increased after fMLP stimulation. In this study, we examined mechanisms of mitochondrial morphology changes after fMLP stimulation. We found that the silencing of mitochondrial fusion protein Mitofusin 2 (MFN2) suppresses mitochondrial morphological changes. Furthermore, MFN2 silencing suppressed OXPHOS activation and chemotaxis upon fMLP stimulation.

Academic Significance and Societal Importance of the Research Achievements

好中球は、感染初期に働く重要な免疫細胞の一つであり、好中球のミトコンドリアの形態異常は、易感染性になる原因の一つとして報告されている。今回、本研究によって、MFN2が、ミトコンドリアの形態変化、酸化的リン酸化、走化性に重要な役割を果たしていることが明らかになった。この知見は、易感染患者にみられる病因遺伝子の発見に貢献するだけでなく、好中球以外の短時間で病原体に応答する生体防御機構を解明するうえで重要な手がかりになると考えられる。

Research Products

• [Journal Article] Cigarette Smoke Extract and Its Cytotoxic Factor Acrolein Inhibit Nitric Oxide Production in Human Vascular Endothelial Cells (2020)
  • Author(s): Horinouchi T., Mazaki Y., Terada K., Miwa S.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 11 Pages: 1804-1809
  • DOI: 10.1248/bpb.b20-00522
  • NAID: 130007934121
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-11-01
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular Ca2+ promotes nitric oxide production via Ca2+-sensing receptor-Gq/11 protein-endothelial nitric oxide synthase signaling in human vascular endothelial cells (2019)
  • Author(s): Horinouchi Takahiro、Mazaki Yuichi、Terada Koji、Miwa Soichi
  • Journal Title: Journal of Pharmacological Sciences Volume: － Issue: 4 Pages: 315-319
  • DOI: 10.1016/j.jphs.2019.06.009
  • Peer Reviewed / Open Access
• [Journal Article] Mitofusin 2 is involved in chemotaxis of neutrophil-like differentiated HL-60 cells (2019)
  • Author(s): Mazaki Yuichi、Takada Shingo、Nio-Kobayashi Junko、Maekawa Satoshi、Higashi Tsunehito、Onodera Yasuhito、Sabe Hisataka
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 513 Issue: 3 Pages: 708-713
  • DOI: 10.1016/j.bbrc.2019.04.037
  • Peer Reviewed / Open Access
• [Journal Article] Ca2+ signal is involved in endothelin-1-induced internalization of endothelin type A receptor expressed in Chinese hamster ovary cells (2019)
  • Author(s): Horinouchi Takahiro、Karki Sarita、Terada Koji、Mazaki Yuichi、Miwa Soichi
  • Journal Title: Journal of Pharmacological Sciences Volume: 140 Issue: 1 Pages: 102-105
  • DOI: 10.1016/j.jphs.2019.03.008
  • Peer Reviewed / Open Access
• [Journal Article] Glutathione and cysteines suppress cytotoxicity of gas phase of cigarette smoke by direct reacting with unsaturated carbonyl compounds in the gas phase (2019)
  • Author(s): Higashi Tsunehito、Elmeligy Enas、Mai Yosuke、Noya Yoichi、Terada Koji、Mazaki Yuichi、Kuge Yuji、Miwa Soichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 509 Issue: 4 Pages: 988-993
  • DOI: 10.1016/j.bbrc.2019.01.040
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Annexin A2 is involved in activation of extracellular signal-regulated kinase upon endothelin-1 stimulation (2019)
  • Author(s): Mazaki Yuichi、Higashi Tsunehito、Horinouchi Takahiro、Miwa Soichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 511 Issue: 1 Pages: 69-72
  • DOI: 10.1016/j.bbrc.2019.02.040
  • Peer Reviewed
• [Journal Article] Endothelin type B receptor interacts with the 78-kDa glucose-regulated protein. (2019)
  • Author(s): Mazaki, Y., Higashi, T., Onodera, Y., Nam, JM., Hashimoto, A., Hashimoto, S., Horinouchi, T., and Miwa, S.
  • Journal Title: FEBS Lett Volume: 593(6) Issue: 6 Pages: 644-651
  • DOI: 10.1002/1873-3468.13347
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chinese herbal medicine Qing-Dai-induced pulmonary arterial hypertension in a patient with ulcerative colitis: A case report and experimental investigation (2019)
  • Author(s): Sato Kazuki、Ohira Hiroshi、Horinouchi Takahiro、Nakaya Toshitaka、Mazaki Yuichi、Sugimoto Ayako、Watanabe Taku、Tsujino Ichizo、Nishimura Masaharu
  • Journal Title: Respiratory Medicine Case Reports Volume: 26 Pages: 265-269
  • DOI: 10.1016/j.rmcr.2019.02.007
  • NAID: 120006626587
  • Peer Reviewed / Open Access
• [Presentation] メラノーマ細胞において、Annexin A2は、エンドセリン-1の刺激によるAKTの活性化に関与する (2021)
  • Author(s): 真崎雄一、東恒仁、堀之内孝広、三輪聡一
  • Organizer: 第94回日本薬理学会
• [Presentation] 好中球様細胞に分化させたHL-60細胞のケモタキシスにおける小胞体とミトコンドリアの接触 (2020)
  • Author(s): 真崎雄一、高田真吾、小林純子、前川聡、東恒仁、小野寺康仁、佐邊壽孝
  • Organizer: 日本分子生物学会第43回大会
• [Presentation] Annexin A2は、エンドセリン-1の刺激によるERKの活性化に関与する (2020)
  • Author(s): 真崎雄一、東恒仁、堀之内孝広、三輪聡一
  • Organizer: 第93回日本薬理学会
• [Presentation] MFN 2は好中球様細胞に分化させたHL-60細胞のケモタキシスに関与する (2019)
  • Author(s): 真崎雄一、高田真吾、小林純子、前川聡、東恒仁、小野寺康仁、佐邊壽孝
  • Organizer: 日本分子生物学会第42回大会
• [Presentation] GRP78はエンドセリンB受容体を介したERKの活性化を促す (2019)
  • Author(s): 7.真崎雄一, 東恒仁, 橋本あり, 橋本茂, 南ジンミン, 小野寺康仁, 堀之内孝広, 三輪聡一
  • Organizer: 第92回日本薬理学会
• [Presentation] GRP78 is involved in endothelin B receptor signaling (2018)
  • Author(s): 真崎雄一, 東恒仁, 堀之内孝広, 橋本あり, 橋本茂, 南ジンミン, 小野寺康仁
  • Organizer: 第70回日本細胞生物学会、第51日本発生生物学会合同大会
• [Presentation] ARF1 activation initiates a regulation circuit for ARF1 and RAC1 activities in GPCR-mediated neutrophil chemotaxis (2018)
  • Author(s): 真崎雄一, 小野寺康仁, 東恒仁, 堀之内孝広, 及川司, 佐邊壽孝
  • Organizer: 日本生物物理学会第55回年会
• [Presentation] エンドセリンB受容体はGRP78と相互作用する (2018)
  • Author(s): 真崎雄一, 東恒仁, 堀之内孝広, 橋本あり, 橋本茂, 南ジンミン, 小野寺康仁
  • Organizer: 日本分子生物学会第28回大会