Perea Valerie, Baron Kelsey R, Dolina Vivian, Aviles Giovanni, Rosarda Jessica D, Guo Xiaoyan, Kampmann Martin, Wiseman R Luke
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
Authors contributed equally.
bioRxiv. 2023 May 17:2023.03.11.532186. doi: 10.1101/2023.03.11.532186.
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）由真核生物翻译起始因子2α（eIF2α）激酶蛋白激酶R样内质网激酶（PERK）、一般控制非抑制性2（GCN2）、血红素调节抑制因子（HRI）和蛋白激酶R（PKR）组成，它们在响应各种损伤时诱导翻译和转录信号传导。PERK信号通路的缺陷会导致线粒体功能障碍，并促成多种疾病的发病机制。我们确定了通过药物激活代偿性eIF2α激酶来挽救ISR信号传导并促进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激活剂常山酮可促进ISR信号传导，并挽救PERK缺陷细胞中的内质网应激敏感性。然而，BtdCPU会诱导线粒体去极化，导致线粒体碎片化并激活OMA1-DELE1-HRI信号轴。相比之下，常山酮可促进线粒体延长和适应性线粒体呼吸，模拟PERK诱导的调节作用。这表明常山酮可以弥补PERK信号通路的缺陷并促进适应性线粒体重塑，凸显了通过药物激活ISR来减轻线粒体功能障碍的可能性，并激发了对高选择性ISR激活剂的探索。
