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- Title
Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis.
- Authors
Abe, Ko; Ikeda, Masataka; Ide, Tomomi; Tadokoro, Tomonori; Miyamoto, Hiroko Deguchi; Furusawa, Shun; Tsutsui, Yoshitomo; Miyake, Ryo; Ishimaru, Kosei; Watanabe, Masatsugu; Matsushima, Shouji; Koumura, Tomoko; Yamada, Ken-ichi; Imai, Hirotaka; Tsutsui, Hiroyuki
- Abstract
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. Defending the heart from doxorubicin: The cardiotoxicity of doxorubicin limits its clinical utility as a cancer therapeutic. Abe et al. investigated how doxorubicin induces an iron-dependent form of cell death called ferroptosis specifically in cardiomyocytes. The authors found that doxorubicin accumulated in mitochondrial DNA in cultured cardiomyocytes and mice in a manner proportional to the amount of mitochondrial DNA. Doxorubicin disrupted heme synthesis in cardiomyocytes, which, in turn, induced mitochondrial iron accumulation that culminated in ferroptosis. Supplying a heme precursor attenuated doxorubicin-induced cardiotoxicity in cultured cardiomyocytes and mice. These results offer a potential strategy to prevent doxorubicin-induced cardiotoxicity and may enable more widespread clinical use of doxorubicin.
- Subjects
DOXORUBICIN; CARDIOTOXICITY; HEME; IRON overload; MITOCHONDRIAL DNA; IRON; CELL death; MYOCARDIAL reperfusion
- Publication
Science Signaling, 2022, Vol 15, Issue 758, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abn8017