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Ugur, B., Bao, H., Stawarski, M., Duraine, L.R., Zuo, Z., Lin, Y.Q., Neely, G.G., Macleod, G.T., Chapman, E.R., Bellen, H.J. (2017). The Krebs Cycle Enzyme Isocitrate Dehydrogenase 3A Couples Mitochondrial Metabolism to Synaptic Transmission.  Cell Rep. 21(13): 3794--3806.
FlyBase ID
FBrf0239961
Publication Type
Research paper
Abstract

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.

PubMed ID
PubMed Central ID
PMC5747319 (PMC) (EuropePMC)
Related Publication(s)
Personal communication to FlyBase

Idh3a[1] and Idh3a[A].
Ugur, 2018.10.23, Idh3a[1] and Idh3a[A]. [FBrf0240461]

P{UAS-Gerry}attP2.
Bellen, 2018.10.24, P{UAS-Gerry}attP2. [FBrf0240463]

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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Cell Rep.
    Title
    Cell reports
    ISBN/ISSN
    2211-1247
    Data From Reference