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Details on Person Mitochondrial stress caused by depolarization of the mitocho...
| Class:Id | Summation:9840674 |
|---|---|
| _displayName | Mitochondrial stress caused by depolarization of the mitocho... |
| _timestamp | 2023-10-21 08:23:37 |
| created | [InstanceEdit:9840673] May, Bruce, 2023-07-23 |
| modified | [InstanceEdit:9840709] May, Bruce, 2023-07-25 [InstanceEdit:9840734] May, Bruce, 2023-07-25 [InstanceEdit:9840735] May, Bruce, 2023-07-25 [InstanceEdit:9840787] May, Bruce, 2023-07-26 [InstanceEdit:9851305] May, Bruce, 2023-10-21 |
| text | Mitochondrial stress caused by depolarization of the mitochondrial inner membrane, inhibition of proton flux across the mitochondrial inner membrane, or insufficient protein import capacity caused by inhibition of ATP synthase or iron deficiency is communicated to the cytosol and nucleus, resulting in decreased protein production and increased transcription of chaperones and metabolic genes among others. This pathway is known as the mitochondrial stress response and is a part of mitochondrial signaling and the integrated stress response (Reviewed in Eckl et al. 2021, Picard and Shirihai 2022, Lu et al. 2022, Liu and Birsoy 2023). The mitochondrial stress response participates in adapting cells to harsher environments and, hence, plays a role in tumor progression and metastasis (reviewed in Lee et al. 2022). In unstressed mitochondria, DELE1 is constitutively imported into the mitochondrial matrix and degraded by the LONP1 ATP-dependent protease (Fessler et al. 2022, Sekine et al. 2023). Mitochondrial stress inhibits the complete transit of DELE1 into the matrix and activates the inner membrane protease OMA1 by self-cleavage (Fessler et al. 2022, Sekine et al. 2023, inferred from the mouse Oma1 homolog in Baker et al. 2014, Zhang et al. 2014). Activated OMA1 cleaves the N-terminal region of DELE1 on the outer face of the inner membrane as DELE1 is unable to fully cross the inner membrane (Fessler et al. 2020, Guo et al. 2020, Fessler et al. 2022). The resulting C-terminal fragment of DELE1 egresses from the intermembrane space to the cytosol where it oligomerizes to form an octamer (Yang et al. 2023) which binds and activates EIF2AK1, a constituent kinase of the integrated stress response that phosphorylates EIF2S1, the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2) (Fessler et al. 2020, Guo et al. 2020, Cheng et al. 2022). Phosphorylation of EIF2S1 inhibits general translation but increases translation of specific mRNAs that possess upstream open reading frames (reviewed in Wek 2018). Among these mRNAs are the transcription factors DDIT3 (CHOP), ATF4, and ATF5, which activate expression of chaperone genes among others. |
| (summation) | [Pathway:9840373] Cellular response to mitochondrial stress [Homo sapiens] |
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