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

Abstract

Neurotransmission is a tightly regulated Ca 2+ -dependent process. Upon Ca 2+ 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. Ugur et al. find that loss of the mitochondrial enzyme IDH3A leads to a reduction in alpha-ketoglutarate (αKG) and impairs synaptic transmission through an ATP-independent pathway. idh3a mutants phenocopy loss of the Ca 2+ sensor syt1 at neuromuscular junctions, and αKG promotes membrane fusion by enhancing Syt1-lipid interaction in vitro.