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Review
. 2025 Aug 13;16(8):957.
doi: 10.3390/genes16080957.

Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology

Jisu Jeong  1   2 , Junghyun Kim  3 , Man S Kim  1   2
Affiliations
Review

Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology

Jisu Jeong et al. Genes (Basel). .

Abstract

Background: The mitochondrial integrated stress response (ISR) represents a fundamental cellular adaptation mechanism with dual protective and pathological roles. We critically analyzed current literature on ISR mechanisms, focusing on recent paradigm shifts including the 2020 discovery of the OMA1-DELE1-HRI axis, emerging controversies over context-dependent activation patterns, and the January 2025 clinical trial failures that have reshaped the therapeutic landscape.

Methods: We reviewed recent literature (2020-2025) examining ISR mechanisms, clinical trials, and therapeutic developments through comprehensive database searches.

Results: The field has evolved from simple linear pathway models to recognition of complex, context-dependent networks. Recent findings reveal that ISR activation mechanisms vary dramatically based on cellular metabolic state, with distinct pathways operating in proliferating versus differentiated cells. The "dark microglia" phenotype in neurodegeneration and DR5-mediated apoptotic switches exemplify pathological ISR manifestations, while adaptive responses include metabolic reprogramming and quality control enhancement.

Conclusions: The 2025 failures of DNL343 and ABBV-CLS-7262 in ALS trials underscore the need for precision medicine approaches that account for context-dependent ISR functions, temporal dynamics, and disease-specific mechanisms.

Keywords: cellular adaptation; eIF2α phosphorylation; integrated stress response; mitochondrial dysfunction; neurodegeneration; precision medicine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
DR5-Mediated Apoptotic Switch in Pathological ISR Activation. The integrated stress response (ISR) operates as a molecular switch determining cell fate based on eIF2α phosphorylation levels. Under mild stress (left), low eIF2α-P activates ATF4 for adaptive cell survival responses. When eIF2α phosphorylation exceeds critical thresholds (>5-fold, right), sustained ATF4 activation leads to massive CHOP upregulation (>10-fold). CHOP directly upregulates DR5 expression, leading to DR5 accumulation in the Golgi apparatus and ligand-independent activation of the extrinsic apoptotic pathway. This quantitative threshold mechanism explains how the same ISR pathway promotes either cellular protection or programmed cell death, representing the ISR’s dual nature as both cellular guardian and executioner. Created in BioRender. (2025) https://BioRender.com/f6won2a (accessed on 31 July 2025).
Figure 2
Figure 2
Context-dependent ISR signaling across disease categories. ISR operates through common eIF2α phosphorylation but produces distinct outcomes across diseases. In neurodegeneration, ISR contributes to protein pathology (tau, TDP-43/SOD1 aggregation) and cellular dysfunction (dark microglia, mitochondrial damage). In cancer, ISR shows dual roles as tumor suppressor (early) or promoter (advanced), with metabolic reprogramming enabling cancer cell cooperation. In metabolic disorders, ISR causes organ-specific dysfunction through β-cell apoptosis, vascular calcification, and systemic insulin resistance. This context-dependency necessitates disease-specific therapeutic approaches. Created in BioRender. (2025) https://BioRender.com/f6won2a (accessed on 31 July 2025).
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References

    1. Harding H.P., Novoa I., Zhang Y., Zeng H., Wek R.C., Schapira M., Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell. 2000;6:1099–1108. doi: 10.1016/S1097-2765(00)00108-8. - DOI - PubMed
    1. Dever T.E., Feng L., Wek R.C., Cigan A.M., Donahue T.F., Hinnebusch A.G. Phosphorylation of initiation factor 2α by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell. 1992;68:585–596. doi: 10.1016/0092-8674(92)90193-G. - DOI - PubMed
    1. Harding H.P., Zhang Y., Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999;397:271–274. doi: 10.1038/16729. - DOI - PubMed
    1. Meurs E., Chong K., Galabru J., Thomas N.S., Kerr I.M., Williams B.R., Hovanessian A.G. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell. 1990;62:379–390. doi: 10.1016/0092-8674(90)90374-N. - DOI - PubMed
    1. Levin D., Ranu R.S., Ernst V., London I.M. Regulation of protein synthesis in reticulocyte lysates: Phosphorylation of methionyl-tRNAf binding factor by protein kinase activity of translational inhibitor. Proc. Natl. Acad. Sci. USA. 1976;73:3112–3116. doi: 10.1073/pnas.73.9.3112. - DOI - PMC - PubMed

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