Rheb modulates mTORC1-independent metabolism is essential for lysosomal function in microglia

Microglia are highly motile cells that respond to neuroinflammation and play a crucial role in maintaining CNS homeostasis through their degradation capacity. While metabolic flexibility is vital for peripheral immune cells to sustain cellular function, the adaptation of microglial metabolism to support degradation remains unexplored. In this study, we elucidate key metabolic regulatory mechanisms influencing the transcriptional activity in microglia. The loss of Rheb, an activator of mTOR, leads to reduced histone H3 acetylation, resulting in decreased transcription of lysosome-related genes and diminished degradation capacity. Conversely, inhibition of mTORC1 by Mios/GATOR2 or Torin1 enhances microglial lysosomal function, indicating that Rheb regulates lysosome biogenesis independently of mTORC1. Our transcriptional and metabolic profiling reveals that Rheb deficiency prompts microglia to increase glycolysis and glutaminolysis to compensate for a disrupted TCA cycle under environmental challenges. This impaired TCA cycle, correlated with epigenetic modifications, reduces microglia’s ability to clear myelin debris. In contrast, overexpression of Rheb in microglia enhances fAβ clearance in vivo. Our findings demonstrate that metabolic regulation of lysosomal function in microglia is critical for degradation, and enhancing this process offers therapeutic potential for treating age-related neuroinflammatory conditions.