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

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.