The Krebs Cycle Enzyme Isocitrate Dehydrogenase 3A Couples Mitochondrial Metabolism to Synaptic Transmission

Cell Rep. 2017 Dec 26;21(13):3794-3806. doi: 10.1016/j.celrep.2017.12.005.


Neurotransmission is a tightly regulated Ca2+-dependent process. Upon Ca2+ influx, Synaptotagmin1 (Syt1) promotes fusion of synaptic vesicles (SVs) with the plasma membrane. This requires regulation at multiple levels, but the role of metabolites in SV release is unclear. Here, we uncover a role for isocitrate dehydrogenase 3a (idh3a), a Krebs cycle enzyme, in neurotransmission. Loss of idh3a leads to a reduction of the metabolite, alpha-ketoglutarate (αKG), causing defects in synaptic transmission similar to the loss of syt1. Supplementing idh3a flies with αKG suppresses these defects through an ATP or neurotransmitter-independent mechanism. Indeed, αKG, but not glutamate, enhances Syt1-dependent fusion in a reconstitution assay. αKG promotes interaction between the C2-domains of Syt1 and phospholipids. The data reveal conserved metabolic regulation of synaptic transmission via αKG. Our studies provide a synaptic role for αKG, a metabolite that has been proposed as a treatment for aging and neurodegenerative disorders.

Keywords: Syt1; TCA; alpha-ketoglutarate; endocytosis; exocytosis; synaptotagmin; tricarboxylic acid cycle; αKG.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Calcium / metabolism
  • Citric Acid Cycle*
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / enzymology*
  • Drosophila melanogaster / physiology*
  • Drosophila melanogaster / ultrastructure
  • Isocitrate Dehydrogenase / metabolism*
  • Ketoglutaric Acids / metabolism
  • Larva / metabolism
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Neuromuscular Junction / metabolism
  • Neuromuscular Junction / ultrastructure
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / ultrastructure
  • Protein Binding
  • Protein Domains
  • Synaptic Transmission*
  • Synaptic Vesicles / metabolism
  • Synaptic Vesicles / ultrastructure
  • Synaptotagmins / chemistry
  • Synaptotagmins / metabolism


  • Drosophila Proteins
  • Ketoglutaric Acids
  • Synaptotagmins
  • Adenosine Triphosphate
  • Isocitrate Dehydrogenase
  • Calcium