Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis

Ko Abe, Masataka Ikeda, Tomomi Ide, Tomonori Tadokoro, Hiroko Deguchi Miyamoto, Shun Furusawa, Yoshitomo Tsutsui, Ryo Miyake, Kosei Ishimaru, Masatsugu Watanabe, Shouji Matsushima, Tomoko Koumura, Ken Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui

研究成果: ジャーナルへの寄稿学術誌査読

37 被引用数 (Scopus)

抄録

Clinical use of doxorubicin (DOX) is limited because of its cardiotoxicity, referred to as DOX-induced cardiomyopathy (DIC). Mitochondria-dependent ferroptosis, which is triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DIC. Here, we showed that DOX accumulated in mitochondria by intercalating into mitochondrial DNA (mtDNA), inducing ferroptosis in an mtDNA content-dependent manner. In addition, DOX disrupted heme synthesis by decreasing the abundance of 5'-aminolevulinate synthase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron overload and ferroptosis in mitochondria in cultured cardiomyocytes. Alas1 overexpression prevented this outcome. Administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cultured cardiomyocytes and mice suppressed iron overload and lipid peroxidation, thereby preventing DOX-induced ferroptosis and DIC. Our findings reveal that the accumulation of DOX and iron in mitochondria cooperatively induces ferroptosis in cardiomyocytes and suggest that 5-ALA can be used as a potential therapeutic agent for DIC.

本文言語英語
論文番号eabn8017
ジャーナルScience Signaling
15
758
DOI
出版ステータス出版済み - 11月 1 2022

!!!All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 細胞生物学

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