UC San Diego

Neuronal activity consists of a series of molecular events—from action potential firing to synaptic vesicle recycling—which entails high energy input. These energetically expensive processes are supported by glucose flux, followed by consequential glycolytic and mitochondrial ATP generation. However, little is known about how glucose uptake regulates mitochondrial adaptation and its contribution to neuronal activity. Recently, the metabolic sensor enzyme O-GlcNAc transferase (OGT) emerged as a key molecular regulator that signals glucose availability in cells. Here, we first report that O-GlcNAcylation is upregulated by neuronal activity to promote mitochondrial bioenergetics. We demonstrate that disruption in mitochondrial O-GlcNAcylation fails to replenish ATP and compensate for high energy expenditure after neuronal stimulation. Second, we describe that O-GlcNAc modification facilitates proper neuronal excitability from mitochondria that mainly use glucose as opposed to those dependent on ketone bodies. Finally, we show that SIRT5, one of mitochondrial sirtuins, may be O-GlcNAcylated to work as the mediator of the crosstalk between two PTMs—O-GlcNAcylation and succinylation. To sum up, O-GlcNAcylation provides a cue for mitochondria to actively adapt to the new metabolic state in neurons.