Integrated Stress Response Activation Discovered to be Predominant Response to Mitochondrial Dysfunction: A Therapeutic Target Advancement

Overview

Research Institute Our bodies continuously face genetic and developmental stresses and use stress -responsive signaling pathways to promote proteome remodeling. However, these insults result in pathogenesis when persistent upon signaling pathway dysfunction. Additionally, the lack of selective therapeutics has led to considerable interest in defining the molecular mechanisms responsible for regulating cellular proteostasis in response to pathologic insults. As previously discovered, the Unfolded Protein Response regulates glob al cellular physiology in response to endoplasmic reticulum stress. Yet, the UPR is not the only response leading to pathogenesis correction; the Integrated Stress Response is another, involving selective phosphorylation of eIF2α kinases for transcription factor activation. Nonetheless, the ISR's role in etiology mitigation remains largely unknown. Post validation of our gene-set profiling approach using known UPR targets, we monitored the expression of gene-sets regulated downstream of pathways with perturb-seq datasets from K562 cells CRISPRi-depleted of mitochondrial proteostasis factors. We found the ISR predominantly activated in response to broad -scale mitochondrial disruption, and documented novel therapeutic targets: IARS2, PRELID3B, SLC25A42, TIMM23 B, and TOM22. Further, mitochondrial protein processing and targeting were among the notable functions discovered of ISR target genes through Gene Ontology. Our identification of the ISR as the predominant stress-responsive signaling pathway activated by mitochondrial proteotoxic stress underscores a unique opportunity to target the ISR to correct pathologic mitochondrial dysfunction in conditions like type 2 diabetes, the result of β ‐cell anomalies. Ultimately, this viable gene -set profiling approach holds promise for identifying therapeutic targets and biomarkers across the proteome, advancing progress to mitigate cancer, metabolic, and neurodegenerative disease. Connecticut

Competition history

• JSHS 2024 Category not listed

Resources

• National JSHS abstract book ↗

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