Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.

Nature
Xiaoyan GuoMartin Kampmann

Abstract

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 ...Continue Reading

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Datasets Mentioned

BETA
GM25256

Methods Mentioned

BETA
flow cytometry
PCR
transfection
transgenic
super-resolution microscopy
co-immunoprecipitation
fluorescence-activated cell sorting
FACS
Protein Assay
RNA-seq

Software Mentioned

Salmon
Fiji
MaxQuant
Insight3
Treeview
Ensembl
LI
Prism
DESeq2
COR ImageStudio

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