Fig. 1. Hyperglycolysis and glutaminolysis: a response to impaired oxidative glucose metabolism.

Created with BioRender.com 1. Impaired glucose metabolism in neurons necessitates the recruitment of an alternative fuel source for the TCA cycle. 2. In astrocytes, glycolysis metabolizes glucose to form pyruvate. 3. Pyruvate is carboxylated by the enzyme pyruvate carboxylase to form oxaloacetate in a process known as anaplerosis. 4. Oxaloacetate is then used in the TCA cycle to eventually form alpha-ketoglutarate. Alpha-ketoglutarate is converted into glutamate by a transaminase reaction. Within astrocytes, glutamate is then converted into glutamine. 5. Glutamine is released from astrocytes and taken up by neurons, where it can be converted back into glutamate. Glutamate is then converted into alpha-ketoglutarate to replenish TCA cycle intermediates and generate ATP in a process called glutaminolysis. Glucose, β-Hydroxybutyric acid, and glutamate may all serve as energy substrates for the TCA cycle via conversion to TCA cycle intermediates. Under conditions of impaired glucose metabolism, β-Hydroxybutyric acid can be used as an alternative fuel source for the TCA cycle, preventing the need for increased glutamate metabolism and avoiding associated excitotoxicity in the brain. PC pyruvate carboxylase, NAD nicotinamide adenine dinucleotide, FAD flavin adenine dinucleotide, CO₂ carbon dioxide, ATP adenosine triphosphate, ADP Adenosine diphosphate, H₂O dihydrogen monoxide.