Synapses: The Brain’s Energy-Demanding Sites

The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic requirements, the brain primarily uses glucose, which can be metabolized through glycolysis and/or mitochondrial oxidative phosphorylation. The relevance of these two energy production pathways in fulfilling energy at presynaptic terminals has been the subject of recent studies. In this review, we dissect the balance of glycolysis and oxidative phosphorylation to meet synaptic energy demands in both resting and stimulation conditions. Besides ATP output needs, mitochondria at synapse are also important for calcium buffering and regulation of reactive oxygen species. These two mitochondrial-associated pathways, once hampered, impact negatively on neuronal homeostasis and synaptic activity. Therefore, as mitochondria assume a critical role in synaptic homeostasis, it is becoming evident that the synaptic mitochondria population possesses a distinct functional fingerprint compared to other brain mitochondria. Ultimately, dysregulation of synaptic bioenergetics through glycolytic and mitochondrial dysfunctions is increasingly implicated in neurodegenerative disorders, as one of the first hallmarks in several of these diseases are synaptic energy deficits, followed by synapse degeneration.