细胞对线粒体应激的反应
中文名称
通路描述
线粒体应激由线粒体内膜去极化、线粒体内膜质子流抑制或由于抑制 ATP 合酶或缺铁引起的蛋白质导入能力不足引起，该应激信号传递到细胞质和细胞核，导致蛋白质产生减少和促调蛋白及代谢基因转录增加等。该通路被称为线粒体应激反应，是线粒体信号和整合应激反应的一部分 (综述在 Eckl et al. 2021, Picard and Shirihai 2022, Lu et al. 2022, Liu and Birsoy 2023)。线粒体应激反应参与细胞适应更恶劣环境，因此参与肿瘤进展和转移 (综述在 Lee et al. 2022)。在未受刺激的线粒体中，DELE1 持续导入线粒体基质并被 LONP1 ATP 依赖性蛋白酶降解 (Fessler et al. 2022, Sekine et al. 2023)。线粒体应激抑制 DELE1 完全进入基质，并通过自切割激活内质膜蛋白酶 OMA1 (Fessler et al. 2022, Sekine et al. 2023，推断自小鼠 Oma1 同源物 Baker et al. 2014, Zhang et al. 2014)。激活的 OMA1 切割 DELE1 的 N 端区域，位于内膜外侧，因为 DELE1 无法完全穿过内膜 (Fessler et al. 2020, Guo et al. 2020, Fessler et al. 2022)。DELE1 产生的 C 端片段从膜间隙释放到细胞质，在那里它寡聚形成八聚体 (Yang et al. 2023)，该八聚体结合并激活 EIF2AK1，它是整合应激反应中的组成性激酶，磷酸化 EIF2S1，真核翻译起始因子 2 (eIF2) 的α亚基 (Fessler et al. 2020, Guo et al. 2020, Cheng et al. 2022)。EIF2S1 的磷酸化抑制一般翻译，但增加具有上游开放阅读框 (uORF) 的特定 mRNA 的翻译 (综述在 Wek 2018)。在这些 mRNA 中包括转录因子 DDIT3 (CHOP), ATF4 和 ATF5，它们激活促调蛋白等基因的表达。
英文描述
Cellular response to mitochondrial stress 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.
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.
所含基因
9 个基因