Hypoglycemia induces metabolic reprogramming and neurodegeneration through SRF/MRTF-A activation in the brain

Hypoglycemia, a common complication in diabetic patients receiving insulin or hypoglycemic agents, as well as in individuals undergoing prolonged fasting, can cause brain damage; however, the molecular mechanisms underlying this effect remain poorly understood. To shed light on this issue, we investigated the molecular basis of hypoglycemia-induced neurodegeneration using both in vitro and in vivo hypoglycemic models. Starvation-induced hypoglycemia triggers neurodegenerative features in human neurons and glial cells, mirroring those observed in the brains of hypoglycemic mice. Notably, neurons activated a survival mechanism via serum response factor (SRF) and myocardin-related transcription factor A (MRTF-A)-mediated metabolic reprogramming, utilizing extracellular matrix (ECM) components as alternative energy sources. This adaptation led to excessive production of urea cycle by-products, which in turn induced neurodegeneration, astrocyte reactivity, and microglial activation. Importantly, glucose refeeding reversed these neurodegenerative features by deactivating SRF/MRTF-A signaling. Together, our results uncover a neuron-intrinsic mechanism linking glucose deprivation to reversible neurodegeneration via SRF/MRTF-A, offering potential targets for preventing hypoglycemia-associated brain damage.