A mitochondrial iron-responsive pathway regulated by DELE1.
A mitochondrial iron-responsive pathway regulated by DELE1.
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由 DELE1 调节的线粒体铁反应途径。
DOI：
10.1016/j.molcel.2023.05.031
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发表时间：
2023
期刊：
影响因子：
16
通讯作者：
Sekine,Shiori
中科院分区：
文献类型：
--
作者：
Sekine,Yusuke;Houston,Ryan;Eckl,Eva-Maria;Fessler,Evelyn;Narendra,DerekP;Jae,LucasT;Sekine,Shiori
血红素调节激酶HRI在血红素/铁缺乏条件下被激活;然而，其潜在的分子机制尚未完全了解。在这里，我们表明，缺铁诱导的HRI激活需要线粒体蛋白DELE 1。值得注意的是，DELE 1的线粒体输入及其随后的蛋白质稳定性受铁可用性的调节。在稳态条件下，DELE 1在线粒体输入后不久被线粒体基质驻留蛋白酶LONP 1降解。在铁螯合作用后，DELE 1输入被阻止，从而稳定线粒体表面上的DELE 1，以激活HRI介导的整合应激反应（ISR）。在红系细胞模型中，这种DELE 1-HRI-ISR途径的消融增强了铁限制条件下的细胞死亡，表明这种途径在铁需求细胞系中具有细胞保护作用。我们的研究结果强调了DELE 1的线粒体输入调节作为先前未被识别的线粒体铁响应途径的核心组成部分，该途径在铁稳态扰动后激发应激信号。
The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Ablation of this DELE1-HRI-ISR pathway in an erythroid cell model enhances cell death under iron-limited conditions, suggesting a cell-protective role for this pathway in iron-demanding cell lineages. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized mitochondrial iron responsive pathway that elicits stress signaling following perturbation of iron homeostasis.