MARK4 regulates GLUT3 surface expression and neuronal glucose uptake

Brain neurons rely predominantly on glucose as an energy source and express glucose transporter 3 (GLUT3) as their principal glucose transporter. Unlike GLUT4, which undergoes insulin-stimulated membrane translocation in peripheral tissues, GLUT3 mediates largely constitutive and relatively insulin-independent glucose uptake in neurons. Although GLUT3 is essential for neuronal functions, its regulatory mechanisms are not fully understood. Microtubule affinity-regulating kinase 4 (MARK4), a member of the AMP-activated protein kinase-related kinase family, has been implicated in Alzheimer's disease and metabolic regulation in peripheral tissues. Here, we show that MARK4 knockdown in primary neurons reduces GLUT3 surface expression and consequently decreases glucose uptake. While MARK4 knockdown did not alter the intracellular distribution of GLUT3 or mitochondria, it reduced mitochondrial abundance. We further found that MARK4 activity is negatively regulated by the insulin/IGF-1-GSK3β signaling axis in primary neurons. Despite these acute metabolic effects in cultured neurons, Mark4-null mice exhibited no overt morphological abnormalities in the brain. Together, these findings identify MARK4 as a regulator of neuronal glucose uptake by modulating GLUT3 surface expression and suggest that MARK4 functions as a modulatory rather than essential component of neuronal metabolic homeostasis.