Analysis of mitochondrial homeostasis through PINK1 kinase

• Project/Area Number: 25860216
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Okayama University
• Principal Investigator: Murata Hitoshi 岡山大学, 医歯(薬)学総合研究科, 講師 (90579096)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: PINK1 / ミトコンドリア / ストレス / SARM1 / NRF2 / 活性酸素種 / 酸化ストレス / マイトファジー / TRAF6

Outline of Final Research Achievements

We analyzed the mechanism of mitochondrial homeostasis through PINK1 which is one of the causing gene products of Parkinson's disease. In transcriptional regulation, we found that NRF2, an antioxidant transcription factor, regulates PINK1 expression under oxidative stress condition. In post-translational regulation, we found that SARM1 and TRAF6 bind to and stabilize PINK1 through lysine 63 chain ubiquitination. Accumulated PINK1 contributes to damaged mitochondrial degradation and cell survival.

Research Products

• [Journal Article] NRF2 regulates PINK1 expression under oxidative stress conditions (2015)
  • Author(s): Murata H, Takamatsu H, Liu S, Kataoka K, Huh NH, Sakaguchi M.
  • Journal Title: PLoS One Volume: 10 Issue: 11 Pages: e0142438-e0142438
  • DOI: 10.1371/journal.pone.0142438
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DNAX-activating protein 10 (DAP10) membrane adaptor associates with receptor for advanced glycation end products (RAGE) and modulates the RAGE-triggered signaling pathway in human keratinocytes (2014)
  • Author(s): Sakaguchi M, Murata H, Aoyama Y, Hibino T, Putranto EW, Ruma IM, Inoue Y, Sakaguchi Y, Yamamoto K, Kinoshita R, Futami J, Kataoka K, Iwatsuki K, Huh NH
  • Journal Title: J Biol Chem Volume: 289 Issue: 34 Pages: 23389-23402
  • DOI: 10.1074/jbc.m114.573071
  • NAID: 120006333870
  • Peer Reviewed / Open Access
• [Journal Article] Dramatic Increase in Expression of a Transgene by Insertion of Promoters Downstream of the Cargo Gene (2014)
  • Author(s): Sakaguchi M, Watanabe M, Kinoshita R, Kaku H, Ueki H, Futami J, Murata H, Inoue Y, Li SA, Huang P, Putranto EW, Ruma IM, Nasu Y, Kumon H, Huh NH
  • Journal Title: Molecular Biotechnology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria (2013)
  • Author(s): Murata H, Sakaguchi M, Kataoka K, Huh NH
  • Journal Title: Molecular Biology of the Cell Volume: 24 (18) Issue: 18 Pages: 2772-2784
  • DOI: 10.1091/mbc.e13-01-0016
  • Peer Reviewed
• [Presentation] NRF2 pathway activation as a target to counteract mitochondrial dysfunction in Parkinson’s disease. (2015)
  • Author(s): Murata H, Takamatsu H, Huh NH, Sakaguchi M.
  • Organizer: International conference on complex medical engineering
  • Place of Presentation: Okayama
  • Year and Date: 2015-06-18
  • Int'l Joint Research / Invited
• [Presentation] Regulation of PINK1 expression through the NRF2 transcription factor under mitochondrial stress conditions (2014)
  • Author(s): Murata H, Takamatsu H, Huh NH, Sakaguchi M
  • Organizer: Biochemical Society PINK1-Parkin signaling in Parkinson’s disease and beyond
  • Place of Presentation: London, UK
  • Year and Date: 2014-12-02
• [Presentation] Transcriptional regulation of PINK1 by NRF2 under mitochondrial stress conditions (2014)
  • Author(s): 村田等、高松仁志、Liu Sulai、許南浩、阪口政清
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Regulation of cellular stress response by mitochondrial kinase PINK1
  • Author(s): Murata H, Sakaguchi M, Kataoka K, Huh NH
  • Organizer: 第86回日本組織培養学会大会
  • Place of Presentation: つくば市
  • Invited
• [Presentation] TRAF6 and SARM1 regulate PINK1 ubiquitination and stabilization on depolarized mitochondria for mitophagy
  • Author(s): Murata H, Sakaguchi M, Kataoka K, Huh NH
  • Organizer: International symposium on mitochondria 2013
  • Place of Presentation: 東京都 六本木
• [Presentation] PINK1のSARM1、TRAF6との複合体形成及びユビキチン化によるミトコンドリア局在制御とマイトファジー誘導
  • Author(s): 村田等、阪口政清、片岡健、許南浩
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸市
• [Presentation] TRAF6 ubiquitinates and stabilizes PINK1 on the outer membrane of depolarized mitochondria through interaction with SARM1
  • Author(s): Murata H, Sakaguchi M, Kataoka K, Huh NH
  • Organizer: The American Society for Cell Biology 53th Annual Meeting
  • Place of Presentation: New Orleans, USA
• [Patent(Industrial Property Rights)] リン酸化SARM1、抗体、SARM1リン酸化阻害剤、神経変性疾患の予防又は治療薬、スクリーニング方法、SARM1改変体及び使用 (2016)
  • Inventor(s): 村田 等、阪口 政清、木下 理恵、山本 健一
  • Industrial Property Rights Holder: 国立大学法人岡山大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-058130
  • Filing Date: 2016-03-23