Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo

Daniel M. Virga, Stevie Hamilton, Bertha Osei, Abigail Morgan, Parker Kneis, Emiliano Zamponi, Natalie J. Park, Victoria L. Hewitt, David Zhang, Kevin C. Gonzalez, Fiona M. Russell, D. Grahame Hardie, Julien Prudent, Erik Bloss, Attila Losonczy, Franck Polleux (Lead / Corresponding author), Tommy L. Lewis Jr (Lead / Corresponding author)

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Abstract

Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly between the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Ca2+ and Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a signaling pathway underlying the subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise and activity-dependent regulation of mitochondria fission/fusion balance.

Original languageEnglish
Article number2142
Pages (from-to)1-21
Number of pages21
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - 8 Mar 2024

Keywords

  • Neurons/metabolism
  • Pyramidal Cells/physiology
  • Hippocampus
  • Axons/metabolism
  • Mitochondria/metabolism
  • Dendrites/physiology

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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