In mammalian cells, mitochondrial dysfunction triggers the integrated stress 
response, in which the phosphorylation of eukaryotic translation initiation 
factor 2α (eIF2α) results in the induction of the transcription factor ATF41-3. 
However, how mitochondrial stress is relayed to ATF4 is unknown. Here we show 
that HRI is the eIF2α 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 eIF2α kinase activity of HRI. In addition, 
DELE1 is required for ATF4 translation downstream of eIF2α 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.