PT  - JOURNAL ARTICLE
AU  - Lopez-Nieto, Marta
AU  - Sun, Zhaozhi
AU  - Relton, Emily
AU  - Safakli, Rahme
AU  - Freibaum, Brian D.
AU  - Taylor, J Paul
AU  - Ruggieri, Alessia
AU  - Smyrnias, Ioannis
AU  - Locker, Nicolas
TI  - Activation of the mitochondrial unfolded protein response regulates the formation of stress granules
AID  - 10.1101/2023.10.26.564187
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2023.10.26.564187
4099  - http://biorxiv.org/content/early/2024/07/31/2023.10.26.564187.short
4100  - http://biorxiv.org/content/early/2024/07/31/2023.10.26.564187.full
AB  - 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 SGs 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 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 may contribute to restoring mitochondrial functions under stressful conditions.Summary statement We describe a novel crosstalk between the mitochondrial unfolded protein response and the integrated stress response involving stress granules that protects cells from further stress.Competing Interest StatementThe authors have declared no competing interest.