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

Nat Commun. 2018 Nov 27;9(1):5008. doi: 10.1038/s41467-018-07416-2.


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 Ca2+ ([Ca2+]m) uptake during neurotransmission, leading to reduced presynaptic [Ca2+]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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Axons / metabolism*
  • Calcium / metabolism
  • Dendrites / metabolism
  • Female
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Potential, Mitochondrial
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mitochondrial Dynamics*
  • Mitochondrial Proteins / metabolism*
  • Mitochondrial Size*
  • Presynaptic Terminals / metabolism*
  • Pyramidal Cells / metabolism


  • Membrane Proteins
  • Mitochondrial Proteins
  • mitochondrial fission factor, mouse
  • Adenosine Triphosphate
  • Calcium