Mitochondria at the neuronal presynapse in health and disease

Key Points

  • Synaptic communication within the nervous system is a highly energy-demanding process that is tightly regulated by Ca2+ signalling

  • Mitochondria are ideally suited to provide energy to power synaptic function and buffer Ca2+, and they are actively recruited to and from synapses

  • Presynaptic mitochondria are important for providing ATP to support prolonged synaptic activity

  • Presynaptic mitochondria are also capable of buffering presynaptic Ca2+ signals, thereby modulating neurotransmission and potentially placing an upper limit on synaptic activity

  • Greater computational flexibility might be afforded by varying the mitochondrial occupancy of presynapses

  • Dysfunction of presynaptic mitochondria could contribute to neurodegeneration by impairing synaptic homeostasis

Abstract

Synapses enable neurons to communicate with each other and are therefore a prerequisite for normal brain function. Presynaptically, this communication requires energy and generates large fluctuations in calcium concentrations. Mitochondria are optimized for supplying energy and buffering calcium, and they are actively recruited to presynapses. However, not all presynapses contain mitochondria; thus, how might synapses with and without mitochondria differ? Mitochondria are also increasingly recognized to serve additional functions at the presynapse. Here, we discuss the importance of presynaptic mitochondria in maintaining neuronal homeostasis and how dysfunctional presynaptic mitochondria might contribute to the development of disease.

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Figure 1: Schematic of a synapse.
Figure 2: Mitochondrial recruitment to the presynapse.
Figure 3: Generation and consumption of ATP in presynaptic terminals.
Figure 4: Regulation of Ca2+ transients at the presynapse.
Figure 5: Pathogenesis of disease.

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Acknowledgements

The authors apologize to those colleagues whose work could not be cited owing to space limitations. M.J.D. was supported by a Wellcome Trust Clinical Postdoctoral Fellowship (106713/Z/14/Z) and an Academy of Medical Sciences starter grant. This work was further supported by a grant from the Wellcome Trust (093239/Z/10/Z), a European Research Council starting grant 282430 (Fuelling Synapses) and a research prize from the Lister Institute of Preventive Medicine to J.T.K.

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M.J.D. and J.T.K. researched data for the article, discussed the content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Michael J. Devine or Josef T. Kittler.

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Glossary

Mitochondrial matrix

The space within the inner membrane of the mitochondrion, containing the enzymes that facilitate reactions in the citric acid cycle, oxidative phosphorylation, pyruvate oxidation and β-oxidation of fatty acids.

Recycling pool

(RP). Vesicles that are recruited to the active zone once the RRP is depleted and that maintain vesicle release under moderate stimulation.

Reserve pool

A depot of vesicles that are released only during intense stimulation, constituting the majority of vesicles in most presynaptic terminals.

Readily releasable pool

(RRP). The pool of synaptic vesicles that are available for immediate release, being docked at the presynaptic active zone and primed for release.

Retinal bipolar neurons

Cells that connect light-sensitive rods or cones in the retina with ganglion cells.

Mitochondrial permeability transition pore

(MPTP). Formed in the inner membrane of the mitochondrion under certain pathological conditions, increasing mitochondrial membrane permeability, which can lead to mitochondrial swelling and cell death.

Retinal ganglion cells

These cells convey visual information from retinal bipolar cells to the brain.

Wallerian degeneration

The degeneration of an axon distal to the site of an injury.

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Devine, M., Kittler, J. Mitochondria at the neuronal presynapse in health and disease. Nat Rev Neurosci 19, 63–80 (2018). https://doi.org/10.1038/nrn.2017.170

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