Intracellular Energy Controls Dynamics of Stress-induced Ribonucleoprotein Granules Implicated in ALS/FTD

Energy metabolism and membraneless organelles have been implicated in human diseases including neurodegeneration. How energy deficiency regulates ribonucleoprotein particles such as stress granules (SGs) is still unclear. Here we identified a unique type of granules formed under energy deficiency and uncovered the mechanisms by which the dynamics of diverse stressinduced granules are regulated. Severe energy deficiency induced the rapid formation of energy deficiency-induced stress granule (eSGs), whereas moderate energy deficiency delayed the clearance of conventional SGs. The formation of eSGs or the clearance of 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 disruptions in energycontrolled granule dynamics may contribute to the pathogenesis of relevant diseases.