The integrated stress response as a key pathway downstream of mitochondrial dysfunction

IF 2.5 Q2 PHYSIOLOGY
Maria Bilen , Sara Benhammouda , Ruth S Slack , Marc Germain
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引用次数: 8

Abstract

Mitochondrial function is fundamental to maintaining metabolic homeostasis. Alterations in mitochondrial biogenesis, energy production, and dynamics are behind many metabolic diseases affecting particularly the muscular and nervous systems. Therefore, synchronized coordination between organelles is required to sustain homeostasis. The integrated stress response (ISR) is a heavily investigated pathway that allows for communication between organelles, including the mitochondria and the nucleus among others. The ISR slows down protein synthesis in the cytoplasm and modifies the transcriptome in the nucleus following mitochondrial stress. With the help of the ATF4 transcription factor, it promotes metabolic rewiring, amino acid, and antioxidant synthesis to counteract cellular stress. Under chronic stress, the ISR leads to apoptotic cell death. However, the mechanisms as to how the ISR can coordinate cell death and survival depending on the type of insult remain unclear. In this review, we will discuss the mechanisms of activation of the ISR under different mitochondrial dysfunctions. We propose a few mechanisms and factors that contribute to the cell-specific response. Finally, we discuss the role of the ISR in neurodegenerative diseases given the important implications of the mitochondria in maintaining healthy neurological function.

综合应激反应是线粒体功能障碍下游的关键途径
线粒体功能是维持代谢稳态的基础。线粒体生物发生、能量产生和动力学的改变是许多代谢疾病的原因,尤其是影响肌肉和神经系统。因此,维持体内平衡需要细胞器之间的同步协调。综合应激反应(ISR)是一种被广泛研究的途径,它允许细胞器之间的通信,包括线粒体和细胞核等。在线粒体应激后,ISR减慢了细胞质中的蛋白质合成,并改变了细胞核中的转录组。在ATF4转录因子的帮助下,它促进代谢重新布线,氨基酸和抗氧化剂合成,以抵消细胞压力。在慢性应激下,ISR可导致细胞凋亡。然而,ISR如何根据损伤类型协调细胞死亡和存活的机制尚不清楚。在这篇综述中,我们将讨论不同线粒体功能障碍下ISR的激活机制。我们提出了一些机制和因素,有助于细胞特异性反应。最后,鉴于线粒体在维持健康神经功能方面的重要意义,我们讨论了ISR在神经退行性疾病中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Current Opinion in Physiology
Current Opinion in Physiology Medicine-Physiology (medical)
CiteScore
5.80
自引率
0.00%
发文量
52
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