2. Academic Validation
  3. Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules

Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules

  • J Cell Sci. 2025 May 1;138(9):jcs263548. doi: 10.1242/jcs.263548.
Marta Lopez-Nieto 1 2,  Zhaozhi Sun 3,  Emily Relton 1 2,  Rahme Safakli 4,  Brian D Freibaum 5,  J Paul Taylor 5,  Alessia Ruggieri 3,  Ioannis Smyrnias 4,  Nicolas Locker 1 2
Affiliations

Affiliations

  • 1 Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU2 7HX, UK.
  • 2 The Pirbright Institute, Pirbright GU24 0NF, UK.
  • 3 Heidelberg University, Medical Faculty, Centre for Integrative Infectious Disease Research (CIID), Department of Infectious Diseases, Molecular Virology, Heidelberg 69120, Germany.
  • 4 Faculty of Health and Medical Sciences, School of Veterinary Medicine, University of Surrey, Guildford GU2 7HX, UK.
  • 5 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
PMID: 39463355 DOI: 10.1242/jcs.263548
Abstract

To rapidly adapt to harmful changes to their environment, cells activate the integrated stress response (ISR). This results in an adaptive transcriptional and translational rewiring, and the formation of biomolecular condensates named stress granules (SGs), to resolve stress. In addition to this first line of defence, the mitochondrial unfolded protein response (UPRmt) activates a specific transcriptional programme to maintain mitochondrial homeostasis. We present evidence that the SG formation and UPRmt pathways are intertwined and communicate. UPRmt induction results in eIF2α phosphorylation and the initial and transient formation of SGs, which subsequently disassemble. The induction of GADD34 (also known as PPP1R15A) during late UPRmt protects cells from prolonged stress by impairing further assembly of SGs. Furthermore, mitochondrial functions and cellular survival are enhanced during UPRmt activation when SGs are absent, suggesting that UPRmt-induced SGs have an adverse effect on mitochondrial homeostasis. These findings point to a novel crosstalk between SGs and the UPRmt that might contribute to restoring mitochondrial functions under stressful conditions.

Keywords

GADD34; Integrated stress response; Mitochondrial stress response; Stress granules; UPRmt.

Figures
Products