Integrated Stress Response Alters Energy Metabolism in Brain Cells

Energy metabolism is critical for the survival and function of human cells and organs. When cells encounter stress, such as infection, nutrient deficiency, or toxins, they alter their metabolism to adapt to the perturbation. The integrated stress response (ISR) is an intracellular pathway that rewires metabolism to help cells adapt to these disruptions. Dysregulation of the ISR in the brain is associated with neurodegenerative diseases, including Alzheimer’s, making it a potential therapeutic target. Despite its significance, the specific metabolic changes induced by ISR activation and its mechanisms remain poorly understood. Here, we aimed to elucidate these metabolic changes by using optogenetic H4 neuroglioma cells. Using light, optogenetics allows precise triggering of the ISR. By employing stable isotope tracers and liquid chromatography-mass spectrometry, we observed rapid metabolic reprogramming within the first hour following ISR activation.

Our findings revealed altered glucose utilization, shunting it away from glycolysis towards the pentose phosphate pathway (PPP). Glycolysis produces the cellular energy currency ATP, while the PPP generates reducing power. Downstream of glycolysis, cells utilized anaplerosis, which produces carbon backbones for biomass instead of ATP generation. A common phenomenon observed was the decrease in ATP production, matching the reduced energy demand for protein synthesis from ISR activation. These rapid changes suggest the presence of regulatory mechanisms beyond the known transcriptional and translational effects of ISR, which typically cause changes over longer timescales. This knowledge provides new insights into fast-acting metabolic adaptations driven by ISR and underscores its potential as a therapeutic target for treating neurodegenerative diseases.