Mitochondrial dysfunction is signaled to the integrated stress response by OMA1, DELE1 and HRI
| Autor: | M. Almira Correia, Arun P. Wiita, Ruilin Tian, Bret A. Unger, Giovanni Aviles, Xiaoyan Guo, Martin Kampmann, Yi Liu, Yu-Hsiu T. Lin, Ke Xu |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Protease medicine.medical_treatment ATF4 Biology Cleavage (embryo) Blockade Cell biology 03 medical and health sciences Cytosol 0302 clinical medicine medicine Integrated stress response Inner mitochondrial membrane Transcription factor 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/715896 |
| Popis: | In mammalian cells, mitochondrial dysfunction triggers the integrated stress response (ISR), in which eIF2α phosphorylation upregulates the transcription factor ATF4. However, how mitochondrial stress is relayed to the ISR is unknown. We found that HRI is the eIF2α kinase necessary and sufficient for this relay. Using an unbiased CRISPRi screen, we identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease, and DELE1, a little-characterized protein we found to be associated with the inner mitochondrial membrane. Mitochondrial stress stimulates the OMA1-dependent cleavage of DELE1, leading to its accumulation in the cytosol, where it interacts with HRI and activates its eIF2α kinase activity. Blockade of the OMA1-DELE1-HRI pathway is beneficial during some, but not all types of mitochondrial stress, and leads to an alternative response that induces specific molecular chaperones. Therefore, this pathway is a potential therapeutic target enabling fine-tuning of the ISR for beneficial outcomes in diseases involving mitochondrial dysfunction. |
| Databáze: | OpenAIRE |
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