Opportunistic neuronal fuelling

Abstract

Neurons can utilize either glucose or lactate, yet fuel selection during periods of activity remains unresolved. By combining optical monitoring of cytosolic pyruvate and NADH with mathematical modelling, we systematically evaluated mitochondrial fuelling in cultured neurons and acute brain slices. Under substrate concentrations typical of resting brain tissue, neurons rely almost exclusively on glucose, with a minor contribution from pyruvate. However, when extracellular lactate rises to levels mimicking tissue activity, glycolysis is inhibited and lactate becomes a major substrate, irrespective of ongoing neuronal activity. Ultimately, neuronal fuel selection is dictated not by internal energy demand, but by extracellular lactate availability, which fluctuates with local glial metabolism and systemic states such as exercise. These findings redefine our understanding of short-term metabolic flexibility in the brain and underscore the significant yet understudied role of extracellular pyruvate.