Energy Metabolism in Astrocytes: High Rate of Oxidative Metabolism and Spatiotemporal Dependence on Glycolysis/Glycogenolysis

Abstract

Astrocytic energy demand is stimulated by K + and glutamate uptake, signaling processes, responses to neurotransmitters, Ca 2 + fluxes, and filopodial motility. Astrocytes derive energy from glycolytic and oxidative pathways, but respiration, with its high-energy yield, provides most adenosine 5 0 triphosphate (ATP). The proportion of cortical oxidative metabolism attributed to astrocytes (B30%) in in vivo nuclear magnetic resonance (NMR) spectroscopic and autoradiographic studies corresponds to their volume fraction, indicating similar oxidation rates in astrocytes and neurons. Astrocyte-selective expression of pyruvate carboxylase (PC) enables synthesis of glutamate from glucose, accounting for two-thirds of astrocytic glucose degradation via combined pyruvate carboxylation and dehydrogenation. Together, glutamate synthesis and oxidation, including neurotransmitter turnover, generate almost as much energy as direct glucose oxidation. Glycolysis and glycogenolysis are essential for astrocytic responses to increasing energy demand because astrocytic filopodial and lamellipodial extensions, which account for 80% of their surface area, are too narrow to accommodate mitochondria; these processes depend on glycolysis, glycogenolysis, and probably diffusion of ATP and phosphocreatine formed via mitochondrial metabolism to satisfy their energy demands. High glycogen turnover in astrocytic processes may stimulate glucose demand and lactate production because less ATP is generated when glucose is metabolized via glycogen, thereby contributing to the decreased oxygen to glucose utilization ratio during brain activation. Generated lactate can spread from activated astrocytes via low-affinity monocarboxylate transporters and gap junctions, but its subsequent fate is unknown. Astrocytic metabolic compartmentation arises from their complex ultrastructure; astrocytes have high oxidative rates plus dependence on glycolysis and glycogenolysis, and their energetics is underestimated if based solely on glutamate cycling. Keywords: acetate; glucose metabolism; glutamate; neurotransmitters; potassium; pyruvate carboxylation Introduction Astrocytes are More Than HousekeepersRecent studies in many different fields have shown much more active roles of astrocytes in brain function than previously portrayed by their traditionally ascribed 'bystander or housekeeping' functions. Emerging roles of astrocytes include their interactions with the vasculature, neurons, and other astrocytes via signaling, biosynthetic, and transport processes to regulate blood flow, modulate impulse transmission, and synthesize and degrade glucose-derived neurotransmitters, for example, glutamate and g-aminobutyric acid (GABA) (Takano et al, 2006;Hertz and Zielke, 2004;Volterra and Meldolesi, 2005). All of these processes are energyrequiring or dependent on energy-related metabolic pathways, thereby directly linking astrocyte functions, energetics, and metabolite fluxes.The narrow astrocytic surface extensions (lamellae and filopodia, also called peripheral ast...

Astrocytes are ‘Good Scouts’: Being Prepared Also Helps Neighboring Neurons

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Dissociated Expression of Mitochondrial and Cytosolic Creatine Kinases in the Human Brain: A New Perspective on the Role of Creatine in Brain Energy Metabolism

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Persisting Depletion of Brain Glucose following Cortical Spreading Depression, despite Apparent Hyperaemia: Evidence for Risk of an Adverse Effect of Leão's Spreading Depression

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