Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis
Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis
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DOI：
10.1126/scisignal.abn8017
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发表时间：
2022-11-01
影响因子：
7.3
通讯作者：
Tsutsui, Hiroyuki
中科院分区：
文献类型：
--
作者：
Abe, Ko;Ikeda, Masataka;Tsutsui, Hiroyuki
阿霉素（DOX）的临床使用因其心脏毒性而受到限制，称为DOX诱发的心肌病（DIC）。由铁超载和过度脂质过氧化引发的线粒体依赖性铁死亡在 DIC 的进展中起着关键作用。在这里，我们发现 DOX 通过嵌入线粒体 DNA (mtDNA) 中积累在线粒体中，以 mtDNA 含量依赖性方式诱导铁死亡。此外，DOX 通过降低 5'-氨基乙酰丙酸合成酶 1 (Alas1)（该过程中的限速酶）的丰度来破坏血红素合成，从而损害铁的利用，导致培养的心肌细胞中线粒体铁过载和铁死亡。 Alas1 过度表达阻止了这一结果。将 Alas1 的产物 5-氨基乙酰丙酸 (5-ALA) 给予培养的心肌细胞和小鼠可抑制铁超载和脂质过氧化，从而预防 DOX 诱导的铁死亡和 DIC。我们的研究结果表明，DOX 和铁在线粒体中的积累协同诱导心肌细胞的铁死亡，并表明 5-ALA 可用作 DIC 的潜在治疗剂。
Clinical use of doxorubicin (DOX) is limited because of its cardiotoxicity, referred to as DOX-induced cardiomy-opathy (DIC). Mitochondria-dependent ferroptosis, which is triggered by iron overload and excessive lipid per -oxidation, 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 syn-thase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron over-load 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 sup-pressed 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 cardiomyo-cytes and suggest that 5-ALA can be used as a potential therapeutic agent for DIC.