The HRI branch of the integrated stress response selectively triggers mitophagy.
The HRI branch of the integrated stress response selectively triggers mitophagy.
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DOI：
10.1016/j.molcel.2024.01.016
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发表时间：
2024-02
期刊：
影响因子：
16
通讯作者：
Yogaditya Chakrabarty;Zheng Yang;Hsiuchen Chen;David C. Chan
中科院分区：
文献类型：
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作者：
Yogaditya Chakrabarty;Zheng Yang;Hsiuchen Chen;David C. Chan
为了维持线粒体稳态，与细胞的生理状态协调地剔除受损或过量的线粒体。整合应激反应（ISR）是一个识别不同细胞应激（包括线粒体功能障碍）的信号网络。由于四个ISR分支汇聚到共同的输出，目前还不清楚这个网络检测到的线粒体应激是否可以调节线粒体自噬，线粒体的自噬降解。使用全基因组筛选，我们表明，血红素调节抑制剂（HRI）分支的ISR选择性诱导线粒体自噬。HRI分支的激活导致磷酸化真核起始因子2的线粒体定位，这足以诱导线粒体自噬。HRI线粒体自噬途径与帕金森病相关基因PINK1和PARKIN控制的线粒体自噬途径平行运作，并且在机制上不同。因此，HRI重新利用通常用于翻译起始的机制来触发线粒体自噬以响应线粒体损伤。
To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genesPINK1andPARKINand is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.