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. Overall design: Total RNA from 3D-cultured ReN cells under hypoglycemic and steady-fed conditions for 24 and 48 hours was isolated using the QIAzol lysis reagent (79306, Qiagen, Germany). RNA quality was assessed using an Agilent 2100 bioanalyzer (Agilent Technologies, Amstelveen, The Netherlands), and RNA quantification was performed using an ND-2000 spectrophotometer (Thermo Inc., DE, USA).