Ferroptosis is controlled by the coordinated transcriptional regulation of glutathione and labile iron metabolism by the transcription factor BACH1
Ferroptosis is controlled by the coordinated transcriptional regulation of glutathione and labile iron metabolism by the transcription factor BACH1
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DOI：
10.1074/jbc.ra119.009548
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发表时间：
2020-01-03
影响因子：
4.8
通讯作者：
Igarashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Nishizawa, Hironari;Matsumoto, Mitsuyo;Igarashi, Kazuhiko
铁凋亡是一种铁依赖性的程序性细胞死亡事件，其调控机制和生理意义尚不清楚。分析小鼠胚胎成纤维细胞暴露于铁死亡诱导剂erastin的转录反应，我们发现一组与氧化应激保护相关的基因在铁死亡时被诱导。我们认为这些基因的上调会减弱铁衰亡的诱导，并发现转录因子BTB结构域和CNC同源物1 （BACH1）是血红素和铁代谢的调节因子，通过抑制铁衰亡蛋白诱导的保护基因亚群的转录来促进铁衰亡。我们注意到这些基因参与谷胱甘肽的合成或细胞内不稳定铁的代谢，包括谷氨酸-半胱氨酸连接酶修饰子亚基（Gclm）、溶质载体家族7成员11 （Slc7a11）、铁蛋白重链1 （Fth1）、铁蛋白轻链1 （ft1）和溶质载体家族40成员1 （Slc40a1）。先前也有研究表明，铁下垂会诱发心肌病，在这里，我们观察到Bach1（?/?）小鼠比WT小鼠更能抵抗心肌梗死，并且铁螯合剂去铁氧胺（feasirox）抑制铁下垂可降低缺血损伤的严重程度。我们的研究结果表明，BACH1抑制抗不稳定铁诱导的氧化应激的基因，当保护基因的转录诱导和铁介导的损伤积累之间的平衡被破坏时，BACH1在转录水平上刺激铁死亡。我们认为BACH1控制铁下垂诱导的阈值，可能是减轻铁下垂相关疾病（包括心肌梗死）的治疗靶点。
Ferroptosis is an iron-dependent programmed cell death event, whose regulation and physiological significance remain to be elucidated. Analyzing transcriptional responses of mouse embryonic fibroblasts exposed to the ferroptosis inducer erastin, here we found that a set of genes related to oxidative stress protection is induced upon ferroptosis. We considered that up-regulation of these genes attenuates ferroptosis induction and found that the transcription factor BTB domain and CNC homolog 1 (BACH1), a regulator in heme and iron metabolism, promotes ferroptosis by repressing the transcription of a subset of the erastin-induced protective genes. We noted that these genes are involved in the synthesis of GSH or metabolism of intracellular labile iron and include glutamate-cysteine ligase modifier subunit (Gclm), solute carrier family 7 member 11 (Slc7a11), ferritin heavy chain 1 (Fth1), ferritin light chain 1 (Ftl1), and solute carrier family 40 member 1 (Slc40a1). Ferroptosis has also been previously shown to induce cardiomyopathy, and here we observed that Bach1(?/?) mice are more resistant to myocardial infarction than WT mice and that the severity of ischemic injury is decreased by the iron-chelator deferasirox, which suppressed ferroptosis. Our findings suggest that BACH1 represses genes that combat labile iron-induced oxidative stress, and ferroptosis is stimulated at the transcriptional level by BACH1 upon disruption of the balance between the transcriptional induction of protective genes and accumulation of iron-mediated damage. We propose that BACH1 controls the threshold of ferroptosis induction and may represent a therapeutic target for alleviating ferroptosis-related diseases, including myocardial infarction.