Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity.
Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity.
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DOI：
10.1172/jci.insight.169756
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发表时间：
2023-03-22
期刊：
影响因子：
8
通讯作者：
Tsutsui, Hiroyuki
中科院分区：
文献类型：
--
作者：
Tadokoro, Tomonori;Ikeda, Masataka;Ide, Tomomi;Deguchi, Hiroko;Ikeda, Soichiro;Okabe, Kosuke;Ishikita, Akihito;Matsushima, Shouji;Koumura, Tomoko;Yamada, Ken-ichi;Imai, Hirotaka;Tsutsui, Hiroyuki
阿霉素 (DOX) 是一种化疗药物，可引起心脏毒性，称为阿霉素诱导的心肌病 (DIC)。这种心脏毒性通常限制恶性肿瘤的化疗，并与不良预后相关。然而，这种心脏毒性的分子机制尚未完全阐明。在这里，我们发现 DOX 下调谷胱甘肽过氧化物酶 4 (GPx4)，并通过线粒体中的 DOX-Fe2+ 复合物诱导过度的脂质过氧化，导致线粒体依赖性铁死亡；我们还表明，线粒体依赖性铁死亡是 DOX 心脏毒性的主要原因。在 DIC 小鼠中，左心室射血分数显着受损，并在第 14 天诱导纤维化和 TUNEL+ 细胞。此外，铁死亡的内源性调节因子 GPx4 下调，伴随着脂质过氧化物的积累，尤其是在线粒体中。这些心脏损伤在 GPx4 Tg 小鼠中得到改善，在 GPx4 异源缺失小鼠中加剧。在培养的心肌细胞中，GPx4 过表达或靶向线粒体中 Fe2+ 的铁螯合可防止 DOX 诱导的铁死亡，表明 DOX 引发线粒体铁死亡。此外，用ferrostatin-1和zVAD-FMK同时抑制铁死亡和细胞凋亡，完全防止DOX诱导的心肌细胞死亡。我们的研究结果表明，线粒体依赖性铁死亡在 DIC 的进展中起着关键作用，并且铁死亡是 DOX 心脏毒性中调节细胞死亡的主要形式。
Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Here, we show that DOX downregulated glutathione peroxidase 4 (GPx4) and induced excessive lipid peroxidation through DOX-Fe2+ complex in mitochondria, leading to mitochondria-dependent ferroptosis; we also show that mitochondria-dependent ferroptosis is a major cause of DOX cardiotoxicity. In DIC mice, the left ventricular ejection fraction was significantly impaired, and fibrosis and TUNEL+ cells were induced at day 14. Additionally, GPx4, an endogenous regulator of ferroptosis, was downregulated, accompanied by the accumulation of lipid peroxides, especially in mitochondria. These cardiac impairments were ameliorated in GPx4 Tg mice and exacerbated in GPx4 heterodeletion mice. In cultured cardiomyocytes, GPx4 overexpression or iron chelation targeting Fe2+ in mitochondria prevented DOX-induced ferroptosis, demonstrating that DOX triggered ferroptosis in mitochondria. Furthermore, concomitant inhibition of ferroptosis and apoptosis with ferrostatin-1 and zVAD-FMK fully prevented DOX-induced cardiomyocyte death. Our findings suggest that mitochondria-dependent ferroptosis plays a key role in progression of DIC and that ferroptosis is the major form of regulated cell death in DOX cardiotoxicity.
影响因子：
3.4
作者：
Hirayama, Tasuku;Kadota, Satoki;Nagasawa, Hideko
通讯作者：
Nagasawa, Hideko