A novel model for causing senescence via mitochondrial dysfunction by environmental factors

2018 Fiscal Year Final Research Report

• Project/Area Number: 16KT0013
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Neo-Gerontology
• Research Institution: Center for Novel Science Initatives, National Institutes of Natural Sciences (2018); Okazaki Research Facilities, National Institutes of Natural Sciences (2016-2017)
• Principal Investigator: Nishida Motohiro 大学共同利用機関法人自然科学研究機構(新分野創成センター、アストロバイオロジーセンター、生命創成探究, 生命創成探究センター, 教授 (90342641)
• Co-Investigator(Kenkyū-buntansha): 藤井 重元 東北大学, 医学系研究科, 大学院非常勤講師 (00325333) ; 赤池 孝章 東北大学, 医学系研究科, 教授 (20231798) ; 本橋 ほづみ 東北大学, 加齢医学研究所, 教授 (00282351)
• Research Collaborator: Nishimura Akiyuki ; Tanaka Tomohiro ; Nishiyama Kazuhiro
• Project Period (FY): 2016-07-19 – 2019-03-31
• Keywords: ミトコンドリア / 老化 / 心臓 / 環境因子 / レドックス / イオウ

Outline of Final Research Achievements

Mitochondria are dynamic organella that can change its structure and morphology by repeating fission and fussion cycle, and its quality control is essential for maintenance of body health. In this study, we aimed to reveal the influence of environmental factors on mitochondrial quality and early senescence in view of redox signaling, and identify a novel anti-aging drug. We found that dynamin-related protein 1 (Drp1), a mitochondrial fission-promoting protein, forms polysulfide (Cys-SSH) in protein and depolysulfidation of Drp1 by environmental electrophiles triggered Drp1 activation, which led to mitochondrial fission-mediated myocardial early senescence, resulting in causing cardiac vulnerability against hemodynamic load in mice.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

タンパク質に含まれるCysポリイオウ鎖が環境親電子物質の代謝・消去を担う内因性求核物質の実体となり、環境親電子物質曝露の蓄積がミトコンドリア過剰分裂を介して心筋早期老化を誘導するという新たな機構を解明したこと、さらにこれを選択的に抑制する既承認薬シルニジピンが慢性心不全を改善させるという知見をマウスで得たことは基礎・臨床の両面において意義深い。