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MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size

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Lewis, Tommy L., Kwon, Seok-Kyu, Lee, Annie, Shaw, Reuben, Polleux, Franck·2018·Nature Communications
DOI 10.1038/s41467-018-07416-2PMC PMC6258764

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Abstract

Neurons display extreme degrees of polarization, including compartment-specific organelle morphology. In cortical, long-range projecting, pyramidal neurons (PNs), dendritic mitochondria are long and tubular whereas axonal mitochondria display uniformly short length. Here we explored the functional significance of maintaining small mitochondria for axonal development in vitro and in vivo. We report that the Drp1 ‘receptor’ Mitochondrial fission factor (MFF) is required for determining the size of mitochondria entering the axon and then for maintenance of their size along the distal portions of the axon without affecting their trafficking properties, presynaptic capture, membrane potential or ability to generate ATP. Strikingly, this increase in presynaptic mitochondrial size upon MFF downregulation augments their capacity for Ca 2+ ([Ca 2+ ] m ) uptake during neurotransmission, leading to reduced presynaptic [Ca 2+ ] c accumulation, decreased presynaptic release and terminal axon branching. Our results uncover a novel mechanism controlling neurotransmitter release and axon branching through fission-dependent regulation of presynaptic mitochondrial size.

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  • Mitochondria within Ghost Neuron regions retain short, oval morphology characteristic of axonal mitochondria, rather than elongated forms commonly observed in dendrites.

    “Mitochondria within these regions retain their short, oval morphology (Fig. 4B and Fig. S4), characteristic to axonal mitochondria, rather than the elongated forms commonly observed in dendrites25,40.”

    From Ghost Neuron preparation unlocks high-resolution structural mapping of intracellular architecture in axons (2026) · cites this paper as [40]

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Cited by

Sorted by citations

Authors
Lewis, T. L., Kwon, S.-K., Lee, A., Shaw, R., & Polleux, F.
Affiliations
  • Oklahoma Medical Research Foundation (US)
  • Mortimer B. Zuckerman Mind Brain Behavior Institute (US)
  • Salk Institute for Biological Studies (US)
Corresponding author
Polleux, Franck
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-11-27
Volume
9
Issue
1
Pages
5008-5008
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-07416-2
PMC
PMC6258764
OpenAlex
W2949642444
Cited by
260
References
11
Citations by year
2026: 34 · 2025: 37 · 2024: 34 · 2023: 30 · 2022: 39 · 2021: 37 · 2020: 27 · 2019: 21 · 2018: 1
FWCI
7.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Korea Institute of Science and Technology (2E27850)
  • Fondation Roger de Spoelberch
  • National Institutes of Health
  • National Cancer Institute (P01CA120964, P30CA014195, R35CA220538)
  • National Institute of Neurological Disorders and Stroke (R01NS089456, K99NS091526)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mitochondrial fission, mitochondrial fission factor, Drp1, axonal mitochondria, mitochondrial size, presynaptic neurotransmitter release, axon branching, calcium uptake, presynaptic terminals, pyramidal neurons, neuronal polarity, neurotransmitter release
MeSH terms
Adenosine Triphosphate, Animals, Axons, Calcium, Dendrites, Female, Humans, Male, Membrane Proteins, Mice, Inbred C57BL, Presynaptic Terminals, Pyramidal Cells, Mitochondrial Proteins, Membrane Potential, Mitochondrial, Mitochondrial Size, Gene Knockdown Techniques, HEK293 Cells, Mitochondrial Dynamics

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