Proceedings

Role of Integrated Stress Response in Mediating Mitochondrial Unfolded Protein Response during Mitochondrial Dysfunction

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The integrated stress response (ISR) is one of the most conserved cellular stress responses during mitochondrial dysfunction. The keys in the activation of ISR are the phosphorylation of eIF2α and subsequent induction of ATF4. The phosphorylation of eIF2α is caused by the activation of four specific serine/threonine kinases, which are Heme Regulated Inhibitor (HRI), Protein Kinase Ribonucleic Acid Activated (PKR), Protein Kinase Ribonucleic Acid Activated-Like Endoplasmic Reticulum Kinase (PERK), and General Control Nonderepressible 2 (GCN2). Each kinase is activated by its unique stressors or stress environments but their activations eventually merge to the eIF2α phosphorylation and subsequent induction of ATF4. Previous studies have reported that during mitochondrial Unfolded Protein Response (mtUPR), ATF4 is found to be upregulated, suggesting a connection with ISR. In this study, the mediation of mtUPR by ISR is extensively investigated by genetic approach through the modification of eIF2α sequences, and knocking out ATF4. The phosphorylation of eIF2α and ATF4 activation subsequently is found to be involved in mtUPR. The absence of ATF4 causes the mitochondria to be more susceptible to sense stress, resulting in decreased stress response during mitochondrial dysfunction. Furthermore, this study found that the loss of PKR during treatment by GTPP, a specific mtUPR inducer, led to reduced eIF2α phosphorylation and the expression of mtUPR genes, suggesting that the PKR eIF2α-ATF4 axis is activated during mtUPR mediated by ISR.

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Detail Information

Series Title

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Call Number

BM 23-034

Publisher

i3L, Jakarta : i3L, Jakarta., 2023

Collation

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Language

English

ISBN/ISSN

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Classification

NONE

Content Type

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Media Type

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Carrier Type

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Edition

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Subject(s)

Phosphorylation
Integrated Stress Response
Mitochondrial Unfolded Protein Response
ATF4
eIF2α

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