Marta López-Nieto Jordana

Cells rapidly adapt to environmental stress by activating the integrated stress response (ISR). This leads to inhibition of global translation, the condensation of stalled mRNAs with proteins into cytoplasmic biocondensates named stress granules (SGs), and an adaptive transcriptional and translational rewiring to resolve stress. By remodelling cytoplasmic contents and cellular functions, SGs serve as signalling platforms crucial for stress recovery. In addition, the mitochondrial unfolded protein response (UPRmt) activates transcriptional programmes to maintain or restore mitochondrial homeostasis. Whereas the ISR is identified as a central element of the UPRmt in mammalian systems, the communication between SGs and mitochondria during mitochondrial stress remains unexplored.

This thesis uncovers a novel crosstalk between SGs and mitochondria during UPRmt activation. In U2OS cells, UPRmt triggers ISR activation, global translational shutoff, and transient SG formation, which subsequently disassemble at later UPRmt stages. GADD34 upregulation during late UPRmt prevents further assembly of SGs, protecting cells from prolonged stress. Furthermore, the absence of SG scaffolding proteins G3BP1/2 improves mitochondrial dynamics and respiration, reduces mitochondrial reactive oxygen species (mtROS), and enhances cell survival during UPRmt activation. These findings suggest that UPRmt-induced SGs may have an adverse effect on mitochondrial homeostasis.

Expanding on the interplay between stress responses and mitochondrial function, this work also investigates how yellow fever virus (YFV) –which induces ISR and SG assembly– manipulates mitochondria during viral infection. YFV disrupts mitochondrial dynamics and functions and induces oxidative stress during infection while quality control responses such as the UPRmt and antioxidant defences are activated potentially to mitigate this mitochondrial damage. These results highlight a balance between viral-induced mitochondrial stress and host protective mechanisms. Overall, this work demonstrates the pivotal role of SG dynamics in mitochondrial stress and provides insights into mitochondrial manipulation during YFV viral infection, revealing potential therapeutic targets.