当线粒体承受压力时需要CHOP对ISR综合应激反应进行定向调整来适应

Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR

Keywords：CHOP,ISR,mouse, Mitochondria,

关键词：CHOP，ISR，小鼠，线粒体
作者：Kaspar S, Oertlin C, Szczepanowska K, Kukat A, Senft K, Lucas C, Brodesser S, Hatzoglou M, Larsson O, Topisirovic I, Trifunovic A
出版期刊：《Science Advances》（2021/5/26）

Abstract：

In response to disturbed mitochondrial gene expression and protein synthesis, an adaptive transcriptional response sharing a signature of the integrated stress response (ISR) is activated. We report an intricate interplay between three transcription factors regulating the mitochondrial stress response: CHOP, C/EBPβ, and ATF4. We show that CHOP acts as a rheostat that attenuates prolonged ISR, prevents unfavorable metabolic alterations, and postpones the onset of mitochondrial cardiomyopathy. Upon mitochondrial dysfunction, CHOP interaction with C/EBPβ is needed to adjust ATF4 levels, thus preventing overactivation of the ATF4-regulated transcriptional program. Failure of this interaction switches ISR from an acute to a chronic state, leading to early respiratory chain deficiency, energy crisis, and premature death. Therefore, contrary to its previously proposed role as a transcriptional activator of mitochondrial unfolded protein response, our results highlight a role of CHOP in the fine-tuning of mitochondrial ISR in mammals.

文章摘要：

为了响应线粒体基因表达和蛋白质合成受到干扰，一种具有综合应激反应 (ISR) 特征的适应性转录反应被激活。我们报告了调节线粒体应激反应的三种转录因子之间复杂的相互作用：CHOP、C/EBPβ 和 ATF4。我们表明，CHOP 作为一种变阻器，可以减弱长时间的 ISR，防止不利的代谢改变，并延缓线粒体心肌病的发作。在线粒体功能障碍时，需要 CHOP 与 C/EBPβ 相互作用来调节 ATF4 水平，从而防止 ATF4 调节的转录程序的过度激活。这种相互作用的失败将 ISR 从急性状态转变为慢性状态，导致早期呼吸链缺乏、能量危机和过早死亡。因此，与其先前提出的作为线粒体未折叠蛋白反应的转录激活剂的作用相反，我们的研究结果强调了 CHOP 在哺乳动物线粒体 ISR 微调中的作用。

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