Narwal, P.; Swarnakar, S.; K, S.; Fatima, N.; Dastidar, P. G.; Lonare, A.; Singh, J.; Banerjee, A.; Ganji, M.; Joseph, J.; Basu, J. K.; Maharana, S.

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.