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.132747
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发表时间：
2020-05-07
期刊：
影响因子：
8
通讯作者：
Tsutsui, Hiroyuki
中科院分区：
文献类型：
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作者：
Tadokoro, Tomonori;Ikeda, Masataka;Tsutsui, Hiroyuki
阿霉素(DOX)是一种化疗药物，其引起的心脏毒性称为阿霉素所致的心肌病(DIC)。这种心脏毒性往往限制了恶性肿瘤的化疗，并与预后不良有关。然而，这种心脏毒性的分子机制尚未完全阐明。在这里，我们表明DOX下调谷胱甘肽过氧化物酶4(Gpx4)，并通过DOX-Fe2+复合体诱导线粒体过度的脂质过氧化，导致线粒体依赖性铁下垂；我们还表明线粒体依赖性铁下垂是DOX心脏毒性的主要原因。DIC小鼠第14天左室射血分数明显受损，出现纤维化和TUNEL+细胞。此外，铁下垂的内源性调节因子Gpx4表达下调，并伴有脂质过氧化产物的积聚，尤其是在线粒体中。这些心脏损伤在Gpx4转基因小鼠中得到改善，在Gpx4异基因缺失小鼠中加剧。在培养的心肌细胞中，Gpx4的过度表达或针对线粒体中Fe2+的铁络合可阻止DOX诱导的铁下垂，表明DOX引发了线粒体的铁下垂。此外，铁抑素-1和zVAD-FMK同时抑制铁下垂和细胞凋亡，可完全阻止DOX诱导的心肌细胞死亡。我们的研究结果表明，线粒体依赖的铁下垂在DIC的进展中起着关键作用，铁下垂是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.