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Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly
Jose C Casas-Martinez1,2,3, Qin Xia1,4, Penglin Li1,2,3
1Discipline of Physiology, School of Pharmacy and Medical Sciences, University of Galway, Galway, Ireland.
Cell Death and Differentiation
|November 2, 2025
Summary
Mild endoplasmic reticulum stress promotes cell adaptation and longevity via enhanced mitochondria-ER communication. This adaptive response, mediated by PERK signaling, improves mitochondrial function and remodelling, but is developmental stage-dependent.
Area of Science:
- Cell Biology
- Mitochondrial Biology
- ER Stress Response
Background:
- Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS) are crucial for cellular homeostasis.
- MERCS regulate calcium transfer, lipid transfer, autophagy, and mitochondrial dynamics.
- ER stress, via the Unfolded Protein Response (UPRER), activates PERK and IRE1 at MERCS.
Purpose of the Study:
- To investigate the role of PERK-mediated signaling in adaptive ER stress responses.
- To explore the impact of mild ER stress on myogenesis and lifespan.
- To determine the developmental stage-dependency of adaptive ER stress responses.
Main Methods:
- Induction of mild acute ER stress using tunicamycin (TM) in myoblasts and C. elegans embryos.
- Assessed MERCS assembly, mitochondrial turnover, and function.
- Investigated the role of PERK signaling and its interaction with UPRmt.
Main Results:
- Mild ER stress promoted myogenesis and extended lifespan/health-span in a developmental stage-dependent manner.
- Increased MERCS assembly and autophagy were observed in adaptive responses.
- PERK signaling was essential for enhanced mitochondria-ER communication and mitochondrial remodelling.
Conclusions:
- PERK-dependent adaptive ER stress signaling promotes mitochondrial remodelling and improved physiological function.
- Mild ER stress can enhance cellular resilience and longevity.
- Developmental stage critically influences the outcome of ER stress responses.
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