Coupling of GABA Metabolism to Mitochondrial Glucose Phosphorylation

Abstract

Glucose and oxygen (O 2 ) are vital to the brain. Glucose metabolism and mitochondria play a pivotal role in this process, culminating in the increase of reactive O 2 species. Hexokinase (HK) is a key enzyme on glucose metabolism and is coupled to the brain mitochondrial redox modulation by recycling ADP for oxidative phosphorylation (OXPHOS). GABA shunt is an alternative pathway to GABA metabolism that increases succinate levels, a Krebs cycle intermediate. Although glucose and GABA metabolisms are intrinsically connected, their interplay coordinating mitochondrial function is poorly understood. Here, we hypothesize that the HK and the GABA shunt interact to control mitochondrial metabolism differently in the cortex and the hypothalamus. The GABA shunt stimulated mitochondrial O 2 consumption and H 2 O 2 production higher in hypothalamic synaptosomes (HSy) than cortical synaptosomes (CSy). The GABA shunt increased the HK coupled to OXPHOS activity in both population of synaptosomes, but the rate of activation was higher in HSy than CSy. Significantly, malonate and vigabatrin blocked the effects of the GABA shunt in the HK activity coupled to OXPHOS. It indicates that the glucose phosphorylation is linked to GABA and Krebs cycle reactions. Together, these data shed light on the HK and SDH role on the metabolism of each region fed by GABA turnover, which depends on the neurons' metabolic route. KeywordsBrain • Synaptosome • Mitochondria • GABA shunt • Hexokinase • Bioenergetics Abbreviations α-KG Alpha ketoglutarate ΔΨm Mitochondrial membrane potential 2-DG 2-Deoxyglucose Ap5A P1,P5-Di(adenosine-5') pentaphosphate CSy Cortical synaptosome ETS Electron transport system FCCP Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone GABA-t Gamma transaminase GAD Glutamate decarboxylase GDH Glutamate dehydrogenase Glc Glucose G6P Glucose-6-phosphate HK Hexokinase HSy Hypothalamic synaptosome mROS Mitochondrial reactive oxygen species mt-HK Mitochondrial-bound hexokinase NAG N-Acetyl-Glucosamine OXPHOS Oxidative phosphorylation SDH Succinate dehydrogenase SSADH Succinic semialdehyde dehydrogenase Succ Succinate TCA Tricarboxylic acid cycle * Joao Paulo Cavalcanti-de-Albuquerque

Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum

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A Molecular Framework for Autistic Experiences: Mitochondrial Allostatic Load as A Mediator between Autism and Psychopathology

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