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Updated: Sep 10, 2025

Assessing Mitochondrial Function in Sciatic Nerve by High-Resolution Respirometry
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Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology

Jisu Jeong1,2, Junghyun Kim3, Man S Kim1,2

  • 1Translational-Transdisciplinary Research Center, Medical Science Research Institute, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.

Genes
|August 28, 2025
PubMed
Abstract

Insights

The mitochondrial integrated stress response (ISR) is a complex cellular process with both helpful and harmful effects. Recent research highlights its context-dependent nature, crucial for developing precise therapies.

Area of Science:

  • Cellular Biology
  • Stress Response Mechanisms
  • Mitochondrial Function

Background:

  • The mitochondrial integrated stress response (ISR) is a key cellular adaptation with dual roles in protection and pathology.
  • Recent advancements include the 2020 discovery of the OMA1-DELE1-HRI axis and ongoing debates on ISR activation.
  • Clinical trial outcomes in 2025 have significantly impacted the therapeutic strategies for ISR-related conditions.

Purpose of the Study:

  • To critically analyze current literature on mitochondrial ISR mechanisms.
  • To focus on recent paradigm shifts, controversies, and therapeutic developments.
  • To understand the evolving landscape of ISR research and its clinical implications.

Main Methods:

  • Comprehensive literature review of studies published between 2020 and 2025.
  • Examination of ISR mechanisms, clinical trial data, and therapeutic interventions.
  • Database searches to synthesize recent findings in the field.

Main Results:

  • ISR activation is not a linear pathway but a complex, context-dependent network.
  • Mechanisms of ISR activation vary significantly with cellular metabolic state (e.g., proliferating vs. differentiated cells).
  • Pathological ISR manifestations include "dark microglia" in neurodegeneration and DR5-mediated apoptosis; adaptive responses involve metabolic reprogramming and enhanced quality control.

Conclusions:

  • The 2025 clinical trial failures (DNL343, ABBV-CLS-7262) in ALS highlight the limitations of current therapeutic approaches.
  • Precision medicine is essential, requiring consideration of context-dependent ISR functions, temporal dynamics, and disease-specific pathways.
  • Future therapeutic strategies must be tailored to the intricate and varied roles of the mitochondrial ISR.
Keywords:
cellular adaptationeIF2α phosphorylationintegrated stress responsemitochondrial dysfunctionneurodegenerationprecision medicine

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