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:
UPRmt, Stress granules, Integrated stress response, Mitochondrial stress response, GADD34

Author contributions

Conceptualization: M.L.-N., N.L.; Methodology: M.L.-N., Z.S., E.R., R.S., B.D.F., J.P.T., I.S.; Validation: I.S., N.L.; Formal analysis: M.L.-N., Z.S., I.S., N.L.; Investigation: M.L.-N., Z.S., E.R., A.R., N.L.; Data Curation: M.L.-N., Z.S., A.R., N.L.; Writing – original draft preparation: M.L.-N.; Writing – review and editing: E.R., B.D.F., J.P.T., A.R., I.S., N.L.; Visualization: M.L.-N., A.R., N.L.; Supervision: A.R., I.S., N.L.; ; Funding acquisition: A.R., I.S.

Funding

Work in N.L.'s laboratory is supported by the Biotechnology and Biological Sciences Research Council research and strategic grants BB/V014528/1 and BBS/E/PI/230002A. M.L-N. and R.S. are supported by DCSA4 PhD studentships from the University of Surrey. Work in A.R.'s laboratory was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project numbers 240245660 SFB1129 TP13 and 278001972 TRR186 A14. Bioimaging studies are supported by BBSRC Core Capability grant BBS/E/I/00007039.

Data availability

All relevant data can be found within the article and its supplementary information.

Special Issue

This article is part of the Special Issue ‘Cell Biology of Mitochondria’, guest edited by Ana J. Garcia-Saez and Heidi McBride. See related articles at https://journals.biologists.com/jcs/issue/138/9.

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2024
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