RT Journal Article
SR Electronic
T1 Mitochondrial dysfunction is signaled to the integrated stress response by OMA1, DELE1 and HRI
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 715896
DO 10.1101/715896
A1 Xiaoyan Guo
A1 Giovanni Aviles
A1 Yi Liu
A1 Ruilin Tian
A1 Bret A. Unger
A1 Yu-Hsiu T. Lin
A1 Arun P. Wiita
A1 Ke Xu
A1 M. Almira Correia
A1 Martin Kampmann
YR 2019
UL http://biorxiv.org/content/early/2019/07/26/715896.abstract
AB 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.