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

2019 Fiscal Year Final Research Report

• 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
• Keywords: 心筋症 / 心不全 / 薬剤性心筋症 / 抗がん剤

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.

Free Research Field

循環器内科学

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。