The Krebs Cycle Enzyme Isocitrate Dehydrogenase 3A Couples Mitochondrial Metabolism to Synaptic Transmission
Berrak Ugur,
Huan Bao,
Michal Stawarski,
Lita R. Duraine,
Zhongyuan Zuo,
Yong Qi Lin,
G. Gregory Neely,
Gregory T. Macleod,
Edwin R. Chapman,
Hugo J. Bellen
Affiliations
Berrak Ugur
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
Huan Bao
Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA
Michal Stawarski
Department of Biological Sciences and Wilkes Honors College, Florida Atlantic University, Jupiter, FL 33458, USA
Lita R. Duraine
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
Zhongyuan Zuo
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Yong Qi Lin
The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
G. Gregory Neely
The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
Gregory T. Macleod
Department of Biological Sciences and Wilkes Honors College, Florida Atlantic University, Jupiter, FL 33458, USA
Edwin R. Chapman
Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA
Hugo J. Bellen
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
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.
