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

• DOI: 10.1126/scisignal.abn8017
• Publication Date: 2022-11-01T17:58:12Z
• Authors: Ko Abe; Masataka Ikeda; Tomomi Ide; Tomonori Tadokoro; Hiroko Deguchi Mi...; Shun Furusawa; Yoshitomo Tsutsui; Ryo Miyake; Kosei Ishimaru; Masatsugu Watanabe; Shouji Matsushima; Tomoko Koumura; Ken-ichi Yamada; Hirotaka Imai; Hiroyuki Tsutsui
• Keywords: Cardiotoxicity

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