Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Biophysics and Biochemistry and Institute for Neurodegenerative Diseases, UCSF, San Francisco, CA 94158, USA.
Cell Chem Biol. 2023 Dec 21;30(12):1571-1584.e5. doi: 10.1016/j.chembiol.2023.10.006. Epub 2023 Nov 2.
The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly selective ISR activators.
整合应激反应（ISR）包括 PERK、GCN2、HRI 和 PKR 这几种 eIF2α 激酶，它们能够针对各种应激原诱导翻译和转录信号。PERK 信号通路的缺失会导致线粒体功能障碍，并促成多种疾病的发病机制。我们确定了通过药理学激活补偿性 eIF2α 激酶来挽救 ISR 信号通路，并促进 PERK 缺陷细胞中线粒体适应的可能性。我们发现 HRI 激活剂 BtdCPU 和 GCN2 激活剂戊双脒能够促进 ISR 信号通路，并挽救 PERK 缺陷细胞中的内质网应激敏感性。然而，BtdCPU 会引起线粒体去极化，导致线粒体碎片化和 OMA1-DELE1-HRI 信号轴的激活。相比之下，戊双脒则促进线粒体的伸长和适应性的线粒体呼吸，模拟 PERK 诱导的调控。这表明戊双脒可以补偿 PERK 信号通路的缺失，并促进适应性的线粒体重塑，突出了药理学 ISR 激活减轻线粒体功能障碍的潜力，并促使人们去追求高度选择性的 ISR 激活剂。
