Stress Granules Buffers Inflammation by Restricting dsRNA-led Mitochondrial Fragmentation

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.

doi:10.64898/2026.03.23.713569

bioRxiv · 10.64898/2026.03.23.713569

Stress Granules Buffers Inflammation by Restricting dsRNA-led Mitochondrial Fragmentation

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.

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Abstract

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.

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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.. 2026-03-25. Stress Granules Buffers Inflammation by Restricting dsRNA-led Mitochondrial Fragmentation. https://doi.org/10.64898/2026.03.23.713569

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