Integrated regulation of stress responses, autophagy and survival by altered intracellular iron stores.
Integrated regulation of stress responses, autophagy and survival by altered intracellular iron stores.
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通过改变细胞内铁储备来综合调节应激反应、自噬和生存。
DOI：
10.1016/j.redox.2022.102407
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发表时间：
2022-09
期刊：
影响因子：
11.4
通讯作者：
He, Peijian
中科院分区：
文献类型：
--
作者：
Wang, Yunyang;Wang, Mo;Liu, Yunshan;Tao, Hui;Banerjee, Somesh;Srinivasan, Shanthi;Nemeth, Elizabeta;Czaja, Mark J.;He, Peijian
铁是血液生成和各种关键细胞功能所必需的矿物质。在许多疾病和病症中已经越来越多地观察到铁代谢改变，但是仍然缺乏对铁代谢受损的细胞影响的全面和机制性理解。我们研究了铁超载或铁缺乏对细胞应激反应和自噬的影响，这些反应共同调节细胞的稳态和存活。急性铁负荷导致线粒体ROS（mtROS）的产生和损伤，脂质过氧化，自噬通量受损，和铁凋亡增加。铁诱导的线粒体ROS过量产生是脂质过氧化作用增加、自噬受损和铁凋亡诱导的机制。铁过量诱导的铁凋亡是细胞类型依赖性的，并受转录激活因子4（ATF 4）的调节。ATF 4的上调减轻了铁诱导的自噬功能障碍和铁凋亡，而ATF 4表达的沉默损害了自噬并导致mtROS产生增加和铁凋亡。采用自噬缺陷的肝细胞和不同的自噬抑制剂，我们进一步表明，自噬损伤敏化细胞铁诱导的铁凋亡。相反，缺铁激活内质网（ER）应激反应，减少自噬，并诱导细胞凋亡。与缺铁相关的自噬减少是由于ER应激，因为4-苯基丁酸（4-PBA）减少ER应激改善了自噬通量。铁缺乏时自噬减少的机制是由于溶酶体膜蛋白的翻译后成熟受损而破坏了溶酶体的生物合成。总之，铁过量和铁缺乏导致不同形式的细胞应激和死亡，部分通过自噬功能受损的共同机制。
Iron is a mineral essential for blood production and a variety of critical cellular functions. Altered iron metabolism has been increasingly observed in many diseases and disorders, but a comprehensive and mechanistic understanding of the cellular impact of impaired iron metabolism is still lacking. We examined the effects of iron overload or iron deficiency on cellular stress responses and autophagy which collectively regulate cell homeostasis and survival. Acute iron loading led to increased mitochondrial ROS (mtROS) production and damage, lipid peroxidation, impaired autophagic flux, and ferroptosis. Iron-induced mtROS overproduction is the mechanism of increased lipid peroxidation, impaired autophagy, and the induction of ferroptosis. Iron excess-induced ferroptosis was cell-type dependent and regulated by activating transcription factor 4 (ATF4). Upregulation of ATF4 mitigated iron-induced autophagic dysfunction and ferroptosis, whereas silencing of ATF4 expression impaired autophagy and resulted in increased mtROS production and ferroptosis. Employing autophagy-deficient hepatocytes and different autophagy inhibitors, we further showed that autophagic impairment sensitized cells to iron-induced ferroptosis. In contrast, iron deficiency activated the endoplasmic reticulum (ER) stress response, decreased autophagy, and induced apoptosis. Decreased autophagy associated with iron deficiency was due to ER stress, as reduction of ER stress by 4-phenylbutyric acid (4-PBA) improved autophagic flux. The mechanism of decreased autophagy in iron deficiency is a disruption in lysosomal biogenesis due to impaired posttranslational maturation of lysosomal membrane proteins. In conclusion, iron excess and iron deficiency cause different forms of cell stress and death in part through the common mechanism of impaired autophagic function.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
16
作者：
Ganley IG;Wong PM;Gammoh N;Jiang X
通讯作者：
Jiang X
影响因子：
3.7
作者：
Kao JK;Wang SC;Ho LW;Huang SW;Chang SH;Yang RC;Ke YY;Wu CY;Wang JY;Shieh JJ
通讯作者：
Shieh JJ
影响因子：
18.2
作者：
Hoes MF;Grote Beverborg N;Kijlstra JD;Kuipers J;Swinkels DW;Giepmans BNG;Rodenburg RJ;van Veldhuisen DJ;de Boer RA;van der Meer P
通讯作者：
van der Meer P
铁诱导的线粒体 ROS 生成取决于 AMPK 活性
影响因子：
3.5
作者：
Huang, Hui;Chen, Jun;Hu, Yi
通讯作者：
Hu, Yi