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Pharmacologic Activation of an Integrated Stress Response Kinase Promotes Mitochondrial Remodeling
Pharmacologic Activation of an Integrated Stress Response Kinase Promotes Mitochondrial Remodeling
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Length:
20 minutes
Released:
Mar 12, 2023
Format:
Podcast episode
Description
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.03.11.532186v1?rss=1
Authors: Perea, V., Baron, K. R., Dolina, V., Aviles, G., Rosarda, J. D., Guo, X., Kampmann, M., Wiseman, L.
Abstract:
The integrated stress response (ISR) is a network of eIF2alpha kinases, comprising PERK, GCN2, HRI, and PKR, that induce translational and transcriptional signaling in response to diverse insults. The PERK ISR kinase regulates mitochondria in response to endoplasmic reticulum (ER) stress. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activators of other ISR kinases to rescue ISR signaling and promote mitochondrial adaptation in cells lacking PERK. We show that the HRI activator BtdCPU and the GCN2 activator halofuginone activate ISR signaling and restore ER stress sensitivity in Perk-deficient cells. However, these compounds differentially impact mitochondria. BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and ISR activation through the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and altered mitochondrial respiration, mimicking the regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK activity 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.
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Podcast created by Paper Player, LLC
http://biorxiv.org/cgi/content/short/2023.03.11.532186v1?rss=1
Authors: Perea, V., Baron, K. R., Dolina, V., Aviles, G., Rosarda, J. D., Guo, X., Kampmann, M., Wiseman, L.
Abstract:
The integrated stress response (ISR) is a network of eIF2alpha kinases, comprising PERK, GCN2, HRI, and PKR, that induce translational and transcriptional signaling in response to diverse insults. The PERK ISR kinase regulates mitochondria in response to endoplasmic reticulum (ER) stress. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activators of other ISR kinases to rescue ISR signaling and promote mitochondrial adaptation in cells lacking PERK. We show that the HRI activator BtdCPU and the GCN2 activator halofuginone activate ISR signaling and restore ER stress sensitivity in Perk-deficient cells. However, these compounds differentially impact mitochondria. BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and ISR activation through the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and altered mitochondrial respiration, mimicking the regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK activity 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.
Copy rights belong to original authors. Visit the link for more info
Podcast created by Paper Player, LLC
Released:
Mar 12, 2023
Format:
Podcast episode
Titles in the series (100)
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