Abstract
In mammalian cells, mitochondrial dysfunction triggers the integrated stress response, in which the phosphorylation of eukaryotic translation initiation factor 2¥á (eIF2¥á) results in the induction of the transcription factor ATF41,2,3. However, how mitochondrial stress is relayed to ATF4 is unknown. Here we show that HRI is the eIF2¥á kinase that is necessary and sufficient for this relay. In a genome-wide CRISPR interference screen, we identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease; and DELE1, a little-characterized protein that we found was associated with the inner mitochondrial membrane. Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2¥á kinase activity of HRI. In addition, DELE1 is required for ATF4 translation downstream of eIF2¥á phosphorylation. Blockade of the OMA1–DELE1–HRI pathway triggers an alternative response in which specific molecular chaperones are induced. The OMA1–DELE1–HRI pathway therefore represents a potential therapeutic target that could enable fine-tuning of the integrated stress response for beneficial outcomes in diseases that involve mitochondrial dysfunction.