Abstract
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 induced by energy deficiency under physiological conditions and uncovered the mechanisms by which the dynamics of diverse stress-induced granules are regulated. Severe energy deficiency induced the rapid formation of energy deficiency-induced stress granules (eSGs) independently of eIF2α phosphorylation, 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 assembly of the eIF4F complex or RNA condensation, respectively. In neurons or brain organoids derived from patients carrying the C9orf72 repeat expansion associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the eSG formation was enhanced, and the clearance of conventional SGs was impaired. These results reveal a critical role for intracellular energy in the regulation of diverse granules and suggest that disruptions in energy-controlled granule dynamics may contribute to the pathogenesis of relevant diseases.