Open AccessMitochondrial stress is relayed to the cytosol by an OMA1–DELE1–HRI pathway
Author(s) -
Xiaoyan Guo,
Giovanni Aviles,
Yi Liu,
Ruilin Tian,
Bret A. Unger,
Yu-Hsiu T. Lin,
Arun P. Wiita,
Ke Xu,
Maria Almira Correia
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-2078-2
Subject(s) - integrated stress response , eif2 , microbiology and biotechnology , biology , mitochondrion , cytosol , atf4 , mitochondrial fusion , eukaryotic initiation factor , translation (biology) , unfolded protein response , mitochondrial dna , genetics , biochemistry , gene , messenger rna , endoplasmic reticulum , enzyme
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 ATF4 1-3 . 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.