The integrated stress response (ISR) is a cellular mechanism that regulates translation in response to various stress signals, including amino acid deprivation and mitochondrial stress. It involves the phosphorylation of eIF2α, which reduces general mRNA translation but promotes the translation of specific downstream factors, such as ATF4 and GCN4, to initiate adaptive gene expression programs. The ISR plays a critical role in cellular homeostasis and is associated with various diseases, including metabolic, pulmonary, and neurological disorders. Recent studies have expanded our understanding of how the ISR regulates amino acid metabolism and mitochondrial stress responses. The ISR is mediated by several eIF2α kinases, including GCN2, PKR, PERK, and HRI, which respond to different stress conditions. The ISR also regulates the expression of genes involved in amino acid biosynthesis, the one-carbon folate cycle, and redox homeostasis. Additionally, the ISR can be activated through mechanisms independent of eIF2α kinases, such as through the action of mTORC1 or through the stabilization of eIF2B. The ISR is also involved in the regulation of mitochondrial stress responses, with pathways such as the mitochondrial unfolded protein response (mtUPR) playing a role in this process. The ISR has been shown to contribute to the survival of cells under stress conditions, including in models of neurodegenerative diseases and cancer. Overall, the ISR is a complex and multifaceted signaling pathway that plays a critical role in cellular adaptation and disease.The integrated stress response (ISR) is a cellular mechanism that regulates translation in response to various stress signals, including amino acid deprivation and mitochondrial stress. It involves the phosphorylation of eIF2α, which reduces general mRNA translation but promotes the translation of specific downstream factors, such as ATF4 and GCN4, to initiate adaptive gene expression programs. The ISR plays a critical role in cellular homeostasis and is associated with various diseases, including metabolic, pulmonary, and neurological disorders. Recent studies have expanded our understanding of how the ISR regulates amino acid metabolism and mitochondrial stress responses. The ISR is mediated by several eIF2α kinases, including GCN2, PKR, PERK, and HRI, which respond to different stress conditions. The ISR also regulates the expression of genes involved in amino acid biosynthesis, the one-carbon folate cycle, and redox homeostasis. Additionally, the ISR can be activated through mechanisms independent of eIF2α kinases, such as through the action of mTORC1 or through the stabilization of eIF2B. The ISR is also involved in the regulation of mitochondrial stress responses, with pathways such as the mitochondrial unfolded protein response (mtUPR) playing a role in this process. The ISR has been shown to contribute to the survival of cells under stress conditions, including in models of neurodegenerative diseases and cancer. Overall, the ISR is a complex and multifaceted signaling pathway that plays a critical role in cellular adaptation and disease.