Mitochondrial-nuclear coupling by lipid radical visualization technology and its application to the treatment of cardiomyopathy

• Project/Area Number: 17K09582
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kyushu University
• Principal Investigator: Ide Tomomi 九州大学, 医学研究院, 准教授 (90380625)
• Co-Investigator(Kenkyū-buntansha): 池田 昌隆 九州大学, 医学研究院, 学術研究員 (10567382) ; 山田 健一 九州大学, 薬学研究院, 教授 (60346806) ; 筒井 裕之 九州大学, 医学研究院, 教授 (70264017)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 心筋症 / 心不全 / 薬剤性心筋症 / 抗がん剤 / ミトコンドリア / フェロトーシス / 脂質ラジカル / 脂質過酸化 / 脂質 / ラジカル

Outline of Final Research Achievements

Doxorubicin (DOX) induces cardiotoxicity and has a poor prognosis, but its molecular mechanism has not been elucidated. In this study, DIC revealed that expression of GPx4 was suppressed at both the mRNA and protein level in mitochondria and was caused by lipid radical and lipid peroxide accumulation. These cardiac disorders were ameliorated in GPx4 overexpressing mice and exacerbated in GPx4 heterozygous mice, upstream of which was associated with a decrease in GPX4, which is also a regulator of ferrotosis.
We also showed that DOX induces excessive lipid peroxidation via mitochondrial DOX-Fe2 + complex and causes mitochondrial-dependent ferrocytosis, which is a major cause of DOX cardiotoxicity.

Academic Significance and Societal Importance of the Research Achievements

増え続ける癌患者に対してドキソルビシンは以前有効な薬剤の1つとして広く用いられているが、その副作用である心毒性の機序は明らかではなかった。今回、DOX心筋症が、ミトコンドリアにおけるフェロトーシスであることを明らかにし、今後DOX誘発性心筋症の新たな治療ターゲットとなりうることを示すことができた。脂質ラジカル可視化剤によるスクリーニングに展開する予定である。

Research Products

• [Journal Article] Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity (2020)
  • Author(s): Tomonori Tadokoro1, Masataka Ikeda 1, Tomomi Ide 2, Hiroko Deguchi1, Soichiro Ikeda1, Kosuke Okabe, Akihito Ishikita, Shouji Matsushima, Tomoko Koumura, Ken-ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui
  • Journal Title: JCI insight Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Functional loss of DHRS7C induces intracellular Ca2+ overload and myotube enlargement in C2C12 cells via calpain activation (2017)
  • Author(s): Arai Shinobu、Ikeda Masataka、Ide Tomomi、Matsuo Yuka、Fujino Takeo、Hirano Katsuya、Sunagawa Kenji、Tsutsui Hiroyuki
  • Journal Title: American Journal of Physiology-Cell Physiology Volume: 312 Issue: 1 Pages: C29-C39
  • DOI: 10.1152/ajpcell.00090.2016
  • Peer Reviewed / Open Access
• [Presentation] Ferroptosis Plays a Key Role in the Development of Doxorubicin-Induced Cardiomyopathy (2019)
  • Author(s): Tomonori Tadokoro1, Masataka Ikeda1, Tomomi Ide2, Soichiro Ikeda1, Kosuke Okabe1, Akihito Ishikita1, Shouji Matsushima1, Hiroyuki Tsutsui
  • Organizer: 日本循環器学会 学術集会
• [Presentation] Ferroptosis plays a key role in the progression of doxorubicin-induced cardiomyopathy (2018)
  • Author(s): Tomonori Tadokoro1, Masataka Ikeda1, Tomomi Ide2, Soichiro Ikeda1, Kosuke Okabe1, Akihito Ishikita1, Shouji Matsushima1, Hiroyuki Tsutsui
  • Organizer: International Society for Heart Research (ISHR)日本部会 学術集会
• [Presentation] 心不全の性差を考える～糖尿病合併と治療の選択～ (2018)
  • Author(s): 井手友美
  • Organizer: 第11回日本性差医学・医療学会学術集会
  • Invited