A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol

• Published in: Nature (London) Vol. 579; no. 7799; pp. 433 - 437
• Main Authors: Fessler, Evelyn, Eckl, Eva-Maria, Schmitt, Sabine, Mancilla, Igor Alves, Meyer-Bender, Matthias F., Hanf, Monika, Philippou-Massier, Julia, Krebs, Stefan, Zischka, Hans, Jae, Lucas T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2020; Nature Publishing Group
• Subjects: 13/95; 14/63; 45; 45/47; 45/70; 45/91; 631/208/191/1908; 631/80/86/2366; Aging; CCAAT/enhancer-binding protein; Cellular stress response; Cytosol; Cytosol - metabolism; Cytosol - pathology; eIF-2 Kinase - metabolism; Enzyme Activation; Eukaryotic Initiation Factor-2 - metabolism; Genes; Genetic aspects; Genetic screening; Genetics; Genome editing; Genome, Human - genetics; Genomes; Health aspects; Homeostasis; Homology; Humanities and Social Sciences; Humans; Kinases; Localization; Metalloendopeptidases - metabolism; Mitochondria; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Proteins - metabolism; multidisciplinary; Oxidative stress; Perturbation; Phosphorylation; Physiological aspects; Protein Binding; Protein synthesis; Proteins; Regulators; Science; Science (multidisciplinary); Stress (Physiology); Stress, Physiological; Transcription Factor CHOP - metabolism; Transcription factors; Germany
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-2076-4

Mitochondrial fidelity is tightly linked to overall cellular homeostasis and is compromised in ageing and various pathologies
1
–
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 cells
4
,
5
. eIF2α phosphorylation is mediated by the four eIF2α kinases GCN2, HRI, PERK and PKR, which are activated by diverse types of cellular stress
6
. However, the machinery that communicates mitochondrial perturbation to the cytosol to trigger the integrated stress response remains unknown
1
,
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 or adverse depending on the type of mitochondrial perturbation. In addition to the core pathway components, our comparative genetic screening strategy identifies a suite of additional regulators. Together, these findings could be used to inform future strategies to modulate the cellular response to mitochondrial dysfunction in the context of human disease.
Haploid genetic screening of cells under different types of mitochondrial perturbation shows that a pathway involving OMA1, DELE1 and the eIF2α kinase HRI communicates mitochondrial stress to the cytosol to trigger the integrated stress response.