Role of mitophagy in inflammasome activation during COPD pathogenesis.

• Project/Area Number: 25461198
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Shimizu Kenichiro 東京慈恵会医科大学, 医学部, 助教 (80385327)
• Co-Investigator(Kenkyū-buntansha): ARAYA JUN 東京慈恵会医科大学, 医学部, 准教授 (90468679)
• Co-Investigator(Renkei-kenkyūsha): KUWANO KAZUYOSHI 東京慈恵会医科大学, 医学部, 教授 (40205266)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: インフラマソーム / 慢性閉塞性肺疾患 / マイトファジー / ミトコンドリア / 喫煙 / 細胞老化

Outline of Final Research Achievements

Cigarette smoke accelerates epithelial cell senescence in the lung, which has been implicated in COPD pathogenesis. Cigarette smoke extract (CSE) induces mitochondrial damage and ROS production, resulting in inflammasome activation and cellular senescence in human bronchial epithelial cell (HBEC). Mitophagy, a mechanism for maintaining cellular homeostasis by removing damaged mitochondria, is induced by CSE exposure. CSE-induced mitophagy is inhibited by PARK2 kockdown with concomitantly enhanced mitochondrial ROS production and cellular senescence. Inversely, PARK2 overexpression inhibits CSE-induced ROS production and cellular senescence. PARK2 expression levels are decreased in COPD lungs compared with non-COPD lungs. Insufficient mitophagy is a part of the pathogenic sequence of COPD development via increased ROS production, resulting from accumulation of damaged mitochondria.

Research Products

• [Journal Article] PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis. (2015)
  • Author(s): Ito S, Araya J, Kurita Y, Kobayashi K, Takasaka N, Yoshida M, Hara H, Minagawa S, Wakui H, Fujii S, Kojima J, Shimizu K, Numata T, Kawaishi M, Odaka M, Morikawa T, Harada T, Nishimura SL, Kaneko Y, Nakayama K, Kuwano K.
  • Journal Title: Autophagy. Volume: 11 Issue: 3 Pages: 547-59
  • DOI: 10.1080/15548627.2015.1017190
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant