The integrated stress response (ISR) is a signaling network that responds to diverse cellular stresses, including mitochondrial dysfunction. The heme-regulated inhibitor (HRI) branch of the ISR has been shown to be activated by mitochondrial stress, but it was unclear whether this pathway regulates mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, the authors identified multiple components of the ISR, particularly those in the HRI branch, as regulators of mitophagy. They found that activation of the HRI branch results in the mitochondrial localization of phosphorylated eukaryotic initiation factor 2 (p-EIF2α), which is sufficient to induce mitophagy. This pathway operates in parallel with the PINK1/PARKIN-mediated mitophagy pathway and is mechanistically distinct. The study also revealed that HRI repurposes machinery normally used for translational initiation to trigger mitophagy in response to mitochondrial damage. The findings highlight the role of the HRI branch in maintaining mitochondrial homeostasis and provide insights into the regulation of mitophagy.The integrated stress response (ISR) is a signaling network that responds to diverse cellular stresses, including mitochondrial dysfunction. The heme-regulated inhibitor (HRI) branch of the ISR has been shown to be activated by mitochondrial stress, but it was unclear whether this pathway regulates mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, the authors identified multiple components of the ISR, particularly those in the HRI branch, as regulators of mitophagy. They found that activation of the HRI branch results in the mitochondrial localization of phosphorylated eukaryotic initiation factor 2 (p-EIF2α), which is sufficient to induce mitophagy. This pathway operates in parallel with the PINK1/PARKIN-mediated mitophagy pathway and is mechanistically distinct. The study also revealed that HRI repurposes machinery normally used for translational initiation to trigger mitophagy in response to mitochondrial damage. The findings highlight the role of the HRI branch in maintaining mitochondrial homeostasis and provide insights into the regulation of mitophagy.