Activation of glycolysis alleviates mitochondrial impairments caused by social isolation in Drosophila.

Social isolation (SI) in humans can lead to various psychological and physical abnormalities. However, the molecular mechanisms and potential drug treatments for this illness are not well understood. Drosophila, a social organism, exhibits distinct behavioral defects under SI conditions, such as reduced sleep and loss of sugar intake preference. By examining the transcriptional profiles of SI flies, we discovered significant impacts on metabolic pathways. Notably, serotonin (5-HT) levels were reduced in the brains of SI flies. Treatment with 5-HT reversed the behavioral defects in SI flies. 5-HT is known to regulate mitochondrial synthesis in mouse brain, and we found it also enhances mitochondrial biogenesis in flies. Further investigation revealed that the 5-HT receptor subtype was involved in SI behavior. To activate mitochondrial metabolism, we overexpressed phosphoglycerate kinase (Pgk), an enzyme in the glycolytic pathway, in neurons. This overexpression rescued the behavioral defects in SI flies. Additionally, terazosin, an alpha-1 adrenergic receptor antagonist known to activate Pgk, produced a similar rescue effect. Our study elucidates a key principle of SI-induced psychological damage and proposes a drug targeting strategy for future validation.