The HRI branch of the integrated stress response (ISR) selectively triggers mitophagy. The ISR is a signaling network that detects various cellular stresses, including mitochondrial dysfunction. While the four ISR branches converge to common outputs, it remains unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, the study shows that the HRI branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2 (EIF2), which is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease-related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery normally used for translational initiation to trigger mitophagy in response to mitochondrial damage. The study also shows that HRI activation results in mitochondrial localization of phosphorylated EIF2, which is sufficient to trigger mitophagy. The HRI branch is important for other forms of mitophagy, including PINK1/PARKIN-mediated mitophagy and hypoxia-induced mitophagy. The findings suggest that the HRI branch is the only one of the four ISR branches that promotes mitophagy, consistent with its ability to sense mitochondrial stress. The study provides evidence that the HRI branch is essential for mitophagy, and that the HRI pathway has co-opted a translation initiation factor into a second role as a mitophagy signal. The study also shows that the HRI branch is mechanistically distinct from ubiquitin-mediated mitophagy. The results indicate that the HRI branch is important for mitophagy, and that the HRI pathway plays a critical role in a broad range of mitophagy conditions. The study highlights the importance of the HRI branch in mitochondrial quality control and its potential therapeutic implications for neurodegenerative diseases.The HRI branch of the integrated stress response (ISR) selectively triggers mitophagy. The ISR is a signaling network that detects various cellular stresses, including mitochondrial dysfunction. While the four ISR branches converge to common outputs, it remains unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, the study shows that the HRI branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2 (EIF2), which is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease-related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery normally used for translational initiation to trigger mitophagy in response to mitochondrial damage. The study also shows that HRI activation results in mitochondrial localization of phosphorylated EIF2, which is sufficient to trigger mitophagy. The HRI branch is important for other forms of mitophagy, including PINK1/PARKIN-mediated mitophagy and hypoxia-induced mitophagy. The findings suggest that the HRI branch is the only one of the four ISR branches that promotes mitophagy, consistent with its ability to sense mitochondrial stress. The study provides evidence that the HRI branch is essential for mitophagy, and that the HRI pathway has co-opted a translation initiation factor into a second role as a mitophagy signal. The study also shows that the HRI branch is mechanistically distinct from ubiquitin-mediated mitophagy. The results indicate that the HRI branch is important for mitophagy, and that the HRI pathway plays a critical role in a broad range of mitophagy conditions. The study highlights the importance of the HRI branch in mitochondrial quality control and its potential therapeutic implications for neurodegenerative diseases.