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

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 (?KG), causing defects in synaptic transmission similar to the loss of syt1. Supplementing idh3a flies with ?KG suppresses these defects through an ATP or neurotransmitter-independent mechanism. Indeed, ?KG, but not glutamate, enhances Syt1-dependent fusion in a reconstitution assay. ?KG promotes interaction between the C2-domains of Syt1 and phospholipids. The data reveal conserved metabolic regulation of synaptic transmission via ?KG. Our studies provide a synaptic role for ?KG, a metabolite that has been proposed as a treatment for aging and neurodegenerative disorders.

SUBMITTER: Ugur B 

PROVIDER: S-EPMC5747319 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature