Development of a new strategy for treatment of cardiac senescence by targeting mitochondrial dynamics

• Project/Area Number: 26893211
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Kagoshima University
• Principal Investigator: IKEDA YOSHIYUKI 鹿児島大学, 医歯(薬)学総合研究科, 特任講師 (00573023)
• Project Period (FY): 2014-08-29 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 老化 / オートファジー / ミトコンドリア / 循環器 / ｵｰトファジー

Outline of Final Research Achievements

Mitochondria are dynamic organelles that constantly undergo fusion and fission to adapt to changes in the cellular environment. We investigated the role of Dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission in mediating cardiac senescence. Drp1 downregulation induced mitochondrial fusion, accumulation of damaged mitochondria, increased apoptosis and cardia dysfunction in vivo and in vitro. Drp1 downregulation also suppressed autophagy.
Disruption of mitochondrial fission inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac senescence and dysfunction. These results suggest that mitochondrial dynamics may be the target for the treatment of cardiac senescence.

Research Products

• [Journal Article] Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure. (2016)
  • Author(s): Akihiro Shirakabe, Peiyong Zhai, Yoshiyuki Ikeda, Toshiro Saito, Yasuhiro Maejima, Chiao-Po Hsu, Masatoshi Nomura, Kensuke Egashira, Beth Levine, Junichi Sadoshima,
  • Journal Title: Circulation Volume: 133 Issue: 13 Pages: 1249-1263
  • DOI: 10.1161/circulationaha.115.020502
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endogenous Drp1 Mediates Mitochondrial Autophagy and Protects the Heart Agains Energy Stress. (2015)
  • Author(s): Y. Ikeda, A. Shitakabe, Y. Maejeima, P. Zhai, S. Sciarretta, J. Toli, M. Nomura, K.Mihara, K. Egashira, M. Ohnishi, M. Abdellatif and J. Sadoshima
  • Journal Title: Circulation Research Volume: 116 Issue: 2 Pages: 264-278
  • DOI: 10.1161/circresaha.116.303356
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system (2015)
  • Author(s): Yoshiyuki Ikeda, Akihiro Shirakabe, Christopher Brady, Daniela Zablocki, Mitsuru Ohishi, Junichi Sadoshima
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 78 Pages: 116122-116122
  • DOI: 10.1016/j.yjmcc.2014.09.019
  • Peer Reviewed / Open Access
• [Journal Article] New Insights into the Role of Mitochondrial Dynamics and Autophagy during Oxidative Stress and Aging in the Heart (2014)
  • Author(s): Yoshiyuki Ikeda, Sebastiano Sciarretta, Narayani Nagarajan, Speranza Rubattu, Massimo Volpe, Giacomo Frati, and Junichi Sadoshima
  • Journal Title: Oxidative Medicine and Cellular Longevity Volume: 2014 Pages: 1-13
  • DOI: 10.1155/2014/210934
  • Peer Reviewed / Open Access
• [Presentation] シンポジウム：心臓老化とマイトファジー (2015)
  • Author(s): 2.池田義之、大石 充
  • Organizer: 第51回高血圧関連疾患モデル学会
  • Place of Presentation: 大阪府豊中市、千里ライフサイエンスセンター
  • Year and Date: 2015-10-30
  • Invited
• [Presentation] Cardiac Specific Disruption of Dynamin Related Protein-1 Develops Cardiac Dysfunction via Inhibition of Autophagy. (2015)
  • Author(s): 1.Yoshiyuki Ikeda, Junichi Sadoshima, Mitsuru Ohishi.
  • Organizer: 第79回 日本循環器学会総会・学術集会
  • Place of Presentation: 大阪府大阪市、大阪国際会議場
  • Year and Date: 2015-04-24
• [Presentation] Mitochondrial Fission Pays an Essential Role to Induce Stress Resistance in Response to Cardiac Ischemia/Reperfusion via Mitochondrial Autophagy. (2015)
  • Author(s): 2.Yoshiyuki Ikeda, Junichi Sadoshima, Mitsuru Ohishi.
  • Organizer: 第79回 日本循環器学会総会・学術集会
  • Place of Presentation: 大阪府大阪市、大阪国際会議場
  • Year and Date: 2015-04-24
• [Presentation] Mitochondrial Fission Plays a Crucial Role in Cardiomyocyte Adaptation to Energy Stress via Mitophagy. (2014)
  • Author(s): 池田義之
  • Organizer: American Heart Association (AHA) Scientific Session
  • Place of Presentation: シカゴ、USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Prolonged Inhibition of Mitochondrial Fission Enhances Myocardial Injury in Response to Ischemia/Reperfusion. (2014)
  • Author(s): 池田義之
  • Organizer: American Heart Association (AHA) Scientific Session
  • Place of Presentation: シカゴ、USA
  • Year and Date: 2014-11-15 – 2014-11-19