Mechanisms for the maintenance and regulation of axonal energy supply

The unique polarization and high-energy demand of neurons necessitates specialized mechanisms to maintain energy homeostasis throughout the cell, particularly in the distal axon. Mitochondria play a key role in meeting axonal energy demand by generating adenosine triphosphate through oxidative phosphorylation. Recent evidence demonstrates how axonal mitochondrial trafficking and anchoring are coordinated to sense and respond to altered energy requirements. If and when these mechanisms are impacted in pathological conditions, such as injury and neurodegenerative disease, is an emerging research frontier. Recent evidence also suggests that axonal energy demand may be supplemented by local glial cells, including astrocytes and oligodendrocytes. In this review, we provide an updated discussion of how oxidative phosphorylation, aerobic glycolysis, and oligodendrocyte-derived metabolic support contribute to the maintenance of axonal energy homeostasis.