Hexokinase and Glycolysis: Between Brain Cells Life and Death

Abstract: Hexokinase catalyses the first regulatory step of the glycolytic pathway. We can say without any exaggeration that both hexokinase and glycolysis are involved in the control of brain cells' life and death. To perform these pivotal roles, hexokinase occurs in four different isoforms in mammalian cells. Type I isozyme is best suited for energy generation, introducing glucose in glycolysis. In contrast, Type II and Type III isoforms product is directed to generation of NADPH through the pentose phosphate pathway, utilized in biosynthetic processes. Nevertheless, hexokinase has another unique property to accomplish its multiple functions: the capacity for mitochondrial binding. Linked to its role in apoptosis control, the binding of hexokinase inhibits the action of apoptosis inducers, such as Bax, from initiating the release of intramitochondrial proteins. Akt mediates HKII binding to mitochondria. Overexpression of the phosphatase SHIP2 reduces Akt activity and enhances apoptosis, emphasizing the role of hexokinase in cell death. Furthermore, hexokinase also participates in cellular signaling and functional regulation. Adding complexity to this multidimensional enzyme´s attributes, glycolysis occurs in aerobic or anaerobic situations. “Aerobic glycolysis” participates in the control of cell excitability, in synapse formation and neurite growth. Here we provide an overview of the multiple roles of hexokinase and glycolysis in neuronal metabolic association with astrocytes, oligodendrocytes, and microglia. We also provide an update on the role of hexokinase and glycolysis in microglia activation and in brain aging and neurodegenerative diseases.