Intracellular Energy Controls Dynamics of Stress-induced Ribonucleoprotein Granules

Energy metabolism and membraneless organelles have been implicated in human diseases including neurodegeneration. How energy stress regulates ribonucleoprotein particles such as stress granules (SGs) is still unclear. Here we identified a unique type of granules formed under energy stress and uncovered the mechanisms by which the dynamics of diverse stress-induced granules are regulated. Severe energy stress induced the rapid formation of energy-associated stress granules (eSGs), whereas moderate energy stress delayed the clearance of conventional SGs. The formation of eSGs or the clearance of conventional SGs was regulated by the mTOR-4EBP1-eIF4E pathway or eIF4A1, involving eIF4F complex assembly or RNA condensation, respectively. In ALS patients neurons or cortical organoids, the eSG formation was enhanced, and conventional SG clearance was impaired. These results reveal a critical role for intracellular energy in the regulation of diverse granules and suggest that an imbalance in these dynamics may contribute to the pathogenesis of relevant diseases.