A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol.

Nature
Evelyn FesslerLucas T Jae

Abstract

Mitochondrial fidelity is tightly linked to overall cellular homeostasis and is compromised in ageing and various pathologies1-3. 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 cells4,5. eIF2α phosphorylation is mediated by the four eIF2α kinases GCN2, HRI, PERK and PKR, which are activated by diverse types of cellular stress6. However, the machinery that communicates mitochondrial perturbation to the cytosol to trigger the integrated stress response remains unknown1,2,7. Here we combine genome engineering and haploid genetics to unbiasedly identify genes that affect the induction of C/EBP homologous protein (CHOP), a key factor in the integrated stress response. We show that the mitochondrial protease OMA1 and the poorly characterized protein DELE1, together with HRI, constitute the missing pathway that is triggered by mitochondrial stress. Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. Obstruction of this pathway can be beneficial...Continue Reading

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Citations

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Methods Mentioned

BETA
protein folding
perturbation profiling
flow cytometry
confocal microscopy
immunoprecipitation
PCR
gene-trap
FCS
transfection
electrophoresis

Software Mentioned

Dash
STAR mapper
SQL
Python
GraphPad Prism
Galaxy
DESeq2
Bowtie
ZEN
matplotlib

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