Stress Granules Buffers Inflammation by Restricting dsRNA-led Mitochondrial Fragmentation

Stress granules (SGs) are dynamic RNA–RBP condensates that form during stress and inflammation, yet how they modulate inflammatory signalling remains unclear. We uncover a rapid, protective SG-mediated mechanism that preserves mitochondrial integrity. During stress and translation inhibition, mitochondrial fragmentation releases double-stranded RNA (dsRNA), which activates PKR and its downstream effector DRP1, generating a self-amplifying loop of mitochondrial fragmentation and inflammation. We find that released dsRNA nucleates nanoSGs within minutes at ER–mitochondria contact sites—the very sites of mitochondrial division. These nanoSGs grow into macroSGs, effectively sequestering PKR-activating dsRNA from the cytosol. By depleting dsRNA, SGs suppress PKR–DRP1–driven positive-feedback inflammation and maintain mitochondrial integrity and function. Our findings reveal SGs as key guardians of mitochondrial homeostasis and position condensate biology at the centre of chronic mitochondrial-driven inflammation relevant to autoimmunity, ageing, and neurodegenerative disease.