ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation
ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation
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DOI：
10.1038/s41419-019-2064-5
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发表时间：
2019-10-28
影响因子：
9
通讯作者：
Chung, Su Wol
中科院分区：
文献类型：
--
作者：
Park, Eunhee;Chung, Su Wol
铁凋亡是一种新型的程序性细胞死亡，其中细胞内铁的积累促进脂质过氧化，导致细胞死亡。最近，自噬的诱导已被建议在铁凋亡。然而，自噬和铁凋亡之间的关系仍然存在争议，自噬诱导介质仍然未知。在这项研究中，我们证实了自噬确实是由铁凋亡诱导剂erastin诱导的。此外，我们表明，自噬导致铁依赖性铁凋亡的铁蛋白降解和转铁蛋白受体1（TfR 1）的表达诱导，使用野生型和自噬缺陷细胞，BECN 1（+/-）和LC 3B（-/-）。一致的，自噬缺陷引起细胞内铁的耗竭和脂质过氧化反应的减少，导致细胞存活在erastin诱导的铁凋亡。我们进一步确定，自噬是由erastin诱导的活性氧（ROS）在铁凋亡。这些数据提供的证据表明，ROS诱导的自噬是铁凋亡过程中铁蛋白降解和TfR 1表达的关键调节因子。因此，我们的研究有助于我们对铁蛋白过程的理解，也有助于解决与这种现象相关的一些争议。
Ferroptosis is a novel form of programmed cell death in which the accumulation of intracellular iron promotes lipid peroxidation, leading to cell death. Recently, the induction of autophagy has been suggested during ferroptosis. However, this relationship between autophagy and ferroptosis is still controversial and the autophagy-inducing mediator remains unknown. In this study, we confirmed that autophagy is indeed induced by the ferroptosis inducer erastin. Furthermore, we show that autophagy leads to iron-dependent ferroptosis by degradation of ferritin and induction of transferrin receptor 1 (TfR1) expression, using wild-type and autophagy-deficient cells, BECN1(+/-) and LC3B(-/-). Consistently, autophagy deficiency caused depletion of intracellular iron and reduced lipid peroxidation, resulting in cell survival during erastin-induced ferroptosis. We further identified that autophagy was triggered by erastin-induced reactive oxygen species (ROS) in ferroptosis. These data provide evidence that ROS-induced autophagy is a key regulator of ferritin degradation and TfR1 expression during ferroptosis. Our study thus contributes toward our understanding of the ferroptotic processes and also helps resolve some of the controversies associated with this phenomenon.