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

Xiaoyan Guo, Giovanni Aviles, Yi Liu, Ruilin Tian, Bret A. Unger, Yu-Hsiu T. Lin, Arun P. Wiita, Ke Xu, M. Almira Correia and Martin Kampmann ()
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Xiaoyan Guo: University of California, San Francisco
Giovanni Aviles: University of California, San Francisco
Yi Liu: University of California, San Francisco
Ruilin Tian: University of California, San Francisco
Bret A. Unger: Chan Zuckerberg Biohub
Yu-Hsiu T. Lin: University of California, San Francisco
Arun P. Wiita: University of California, San Francisco
Ke Xu: Chan Zuckerberg Biohub
M. Almira Correia: University of California, San Francisco
Martin Kampmann: University of California, San Francisco

Nature, 2020, vol. 579, issue 7799, 427-432

Abstract: 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 dysfunction.

Date: 2020
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DOI: 10.1038/s41586-020-2078-2

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