Synaptic activity imposes large energy demands that are met by local adenosine triphosphate (ATP) synthesis through glycolysis and mitochondrial oxidative phosphorylation. ATP drives action potentials, supports synapse assembly and remodelling, and fuels synaptic vesicle filling and recycling, thus sustaining synaptic transmission. Given their polarized morphological features — including long axons and extensive branching in their terminal regions — neurons face exceptional challenges in maintaining presynaptic energy homeostasis, particularly during intensive synaptic activity. Recent studies have started to uncover the mechanisms and signalling pathways involved in activity-dependent and energy-sensitive regulation of presynaptic energetics, or ‘synaptoenergetics’. These conceptual advances have established the energetic regulation of synaptic efficacy and plasticity as an exciting research field that is relevant to a range of neurological disorders associated with bioenergetic failure and synaptic dysfunction.
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The authors thank the laboratories and scientists who contributed to data and discoveries discussed here, and J. C. Roney for critical reading and editing. The authors apologize to those colleagues whose work could not be cited because of space limitations. This work was supported by the Intramural Research Program of NINDS, NIH ZIA NS003029 and ZIA NS002946 (Z.-H.S.).
The authors declare no competing interests.
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- Action potential
A brief reversal of electrical polarization across the neuronal membrane that results from the opening and closing of voltage-gated ion channels and produces the nerve impulse that permits communication between neurons.
A partial glucose metabolism that occurs in the cytosol or on membrane surfaces. Glycolysis converts a six-carbon glucose into two three-carbon pyruvates, with a net gain of two adenosine triphosphate (ATP) molecules and two NADH molecules. Pyruvate enters the tricarboxylic acid cycle in the mitochondrial matrix or is reduced to lactate.
- Oxidative phosphorylation
Highly efficient energetic metabolism of pyruvate that occurs in the inner mitochondrial membrane. Oxidative phosphorylation generates adenosine triphosphate (ATP) through the electron transport chain and the actions of ATP synthase.
- Synaptic vesicle recycling
A synaptic vesicle cycle that occurs at presynaptic terminals, encompassing synaptic vesicle endocytosis, refilling the vesicle with neurotransmitters, re-formation of synaptic vesicle pools, mobilization to release sites and the release of neurotransmitters via exocytosis.
The status of the bioenergetics processes involved in the generation and consumption of adenosine triphosphate (ATP) at the synapse. Synaptoenergetics is maintained and adapted through activity-dependent and/or energy-sensitive regulation of local energy metabolism to sustain synaptic efficacy and plasticity.
- Electron transport chain
A series of protein complexes residing on the mitochondrial inner membrane that transfer electrons through electron carriers to form a proton gradient that drives the creation of adenosine triphosphate (ATP).
- Tricarboxylic acid (TCA) cycle
A series of enzymatic reactions that occur in a closed loop in the mitochondrial matrix. The TCA cycle completely breaks down glucose and oxidizes acetyl coenzyme A to generate the NADH and FADH2 that are required for the electron transport chain.
- Glycolytic metabolon
A transient protein complex of sequential glycolytic enzymes that enables metabolites to channel directly from one enzyme to the next to catalyse stepwise glycolytic reactions.
- Energy stress
An imbalanced energetic status caused by insufficient adenosine triphosphate (ATP) supply and/or enhanced energy consumption, resulting in an increased adenosine diphosphate (ADP) to ATP ratio.
- Glucose transporter
One of a group of membrane proteins that take glucose from extracellular spaces into cells.
- AMP-activated protein kinase
(AMPK). A master cellular energy stress sensor that is activated when intracellular adenosine triphosphate (ATP) becomes depleted or ATP consumption is elevated.
- Mitochondrial fission and fusion
Mitochondrial membrane dynamic with the ability to join two mitochondria together (fusion) or separate one mitochondrion into two mitochondria (fission) mediated by multiple fusion or fission proteins. Fission and fusion dynamics control mitochondrial morphology and size and maintain mitochondrial integrity, distribution and metabolism.
The selective elimination of damaged mitochondria by the autophagolysosomal system.
- Long-term potentiation
(LTP). A persistent type of synaptic plasticity that induces a long-lasting increase in the efficacy of synaptic transmission.
- Active zones
Specialized synaptic vesicle recycling regions that display an electron-dense thickening of the presynaptic membrane, together with a cluster of synaptic vesicles, in an area that apposes the postsynaptic region.
An invaginated structure of the mitochondrial inner membrane that extends deep into the matrix to increase the functional surface area of the inner membrane for cellular respiration.
- Motor proteins
A class of molecular motors that drive intracellular trafficking of organelles along cytoskeletal filaments by the hydrolysis of adenosine triphosphate (ATP).
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Li, S., Sheng, ZH. Energy matters: presynaptic metabolism and the maintenance of synaptic transmission. Nat Rev Neurosci 23, 4–22 (2022). https://doi.org/10.1038/s41583-021-00535-8