Neuronal glycolysis meets mitophagy to govern organismal wellbeing

Neurons are exceptionally energy-demanding cells but have limited energy storage, relying on a constant supply of fuel and oxygen. Although glucose is the brain's main energy source, neurons reduce glycolysis under normal conditions. This surprising strategy helps to protect mitochondria by preserving nicotinamide-adenine dinucleotide (NAD⁺), a vital cofactor consumed by glycolysis. NAD⁺ is needed for sirtuin-driven mitophagy, a process that removes damaged mitochondria. By saving NAD⁺, neurons can maintain healthy, energy-efficient mitochondria. These mitochondria then use alternative fuels such as lactate and ketone bodies from astrocytes. Here, we discuss the way in which this balance between reduced glycolysis and active mitophagy supports brain function and overall metabolic health, highlighting a sophisticated system that prioritizes mitochondrial quality for long-term cognitive performance and systemic homeostasis.