Hypoglycemia induces brain metabolic reprogramming and neurodegeneration via serum response factor and myocardin-related transcription factor-A

Hypoglycemia is a frequent and potentially severe complication that can result in significant brain injury in individuals with diabetes treated with insulin or other hypoglycemic agents and in those undergoing prolonged fasting. Despite its clinical importance, the molecular mechanisms through which hypoglycemia induces neurodegeneration remain poorly defined. We therefore investigated the molecular and cellular basis of hypoglycemia-induced brain damage using human neuron and glial cell cultures in vitro and hypoglycemic mouse models in vivo. We found that starvation-induced hypoglycemia triggers hallmark neurodegenerative features, such as astrocyte activation and microglial reactivity, that closely resemble those found in the brains of hypoglycemic mouse models. Neurons notably activate an adaptive survival response mediated by serum response factor (SRF) and myocardin-related transcription factor-A (MRTF-A), which drives a metabolic reprogramming process. This shift enables neurons to use extracellular matrix components as alternative energy sources under glucose deprivation. However, this compensatory mechanism results in the excessive accumulation of urea cycle byproducts, which subsequently exacerbates neuronal damage and promotes glial activation. Glucose refeeding remarkably reversed these neurodegenerative features by deactivating SRF/MRTF-A signaling in both in vitro and in vivo. Collectively, our results revealed a neuron-intrinsic mechanism linking glucose deprivation to reversible neurodegeneration via SRF/MRTF-A, offering potential targets for preventing hypoglycemia-associated brain damage.