Pentose Phosphate Pathway Is Critical for Providing Energy by Bypassing 6-Phosphofructo-1-Kinase (PFK1) During Increased Neuronal Activity

Glycolysis and the pentose phosphate pathway (PPP) are two metabolic pathways that play crucial roles in brain energy metabolism. The glycolytic pathway is differentially regulated in neurons compared to astrocytes. In neurons, the flux directly through the glycolytic pathway is reduced due to compromised ability to activate the key glycolytic enzyme 6-phosphofructo-1-kinase (PFK1). Consequently, potential increases in neuronal glucose metabolic flux can occur through the PPP, leading to the generation of NADPH, which is essential for the antioxidant defense system in these cells. Additionally, the PPP can supply glycolysis with intermediates downstream of PFK1, resulting in the production of pyruvate, which is used by mitochondria for oxidative phosphorylation and ATP production. In this review, we propose that during increased activity, neurons will preferentially metabolize glucose through the PPP. This allows them to support their antioxidant defense mechanisms and maintain bioenergetic metabolism by bypassing the limiting PFK1 enzyme and still forming pyruvate for mitochondrial oxidation.