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

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...

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Published in:Science signaling 2022-11, Vol.15 (758), p.eabn8017
Main 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
Format: Article
Language:English
Subjects:
Aminolevulinic Acid - metabolism
Animals
Cardiomyocytes
Cardiotoxicity
Cardiotoxicity - etiology
Cardiotoxicity - metabolism
Cell death
DNA biosynthesis
DNA, Mitochondrial - metabolism
Doxorubicin
Doxorubicin - pharmacology
Ferroptosis
Heme
Heme - metabolism
Iron
Iron - metabolism
Iron Overload - complications
Iron Overload - metabolism
Mice
Mitochondria - genetics
Mitochondrial DNA
Myocytes, Cardiac - metabolism
Synthesis
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Summary: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.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.abn8017