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Mitochondrial Stress Is Transmitted To Cytoplasm Through OmA1-DELE1-HRI Pathway
February 23, 2022
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Mitochondrial stress is transmitted to the cytoplasm via the OMA1-DELE1-HRI pathway. The omA1-DELE1-HRI pathway is mediated by mitochondrial stress.
 Excerpt from Nature's official website
In mammalian cells, mitochondrial dysfunction triggers an integrated stress response, and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) leads to induction of the transcription factor ATF41,2,3. However, how mitochondrial stress is transmitted to ATF4 remains unclear. Here, the authors demonstrate that HRI is an eIF2α kinase, which is a necessary and sufficient relay. In genome-wide CRISPR interference screening, the authors identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease; DELE1, a small number of characteristic proteins associated with the mitochondrial inner membrane.
Mitochondrial stress stimulates the OMA1-dependent cleavage of DELE1, resulting in the accumulation of DELE1 in the cytoplasm and the interaction with HRI to activate the eIF2α kinase activity of HRI. In addition, DELE1 is required for ATF4 translation downstream of eIF2α phosphorylation. Blocking the OMA1 -- DELE1 -- HRI pathway triggers another response that induces specific chaperones.
Therefore, the OMA1-DELE1-HRI pathway is a potential therapeutic target for fine-tuning the comprehensive stress response involved in beneficial outcomes of diseases with mitochondrial dysfunction.
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