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Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
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DELE1, also known as KIAA0141, is a 515 amino acid protein, which localizes in Mitochondrion and is detected in liver, skeletal muscle, kidney, pancreas, spleen, thyroid, testis, ovary, small intestine and colon. DELE1 is essential for the induction of death receptor-mediated apoptosis through the regulation of caspase activation. Mitochondrial malfunction needs to be relayed to the cytosol, where an integrated stress response is triggered by the phosphorylation of eukaryotic translation initiation factor 2α(eIF2α) in mammalian cells. eIF2αphosphorylation is mediated by the four eIF2α kinases GCN2, HRI, PERK and PKR, which are activated by diverse types of cellular stress. 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.