High resolution measurement of the glycolytic rate

Bittner, Carla X.; Loaiza, Anitsi; Ruminot, Iván; Larenas, Valeria; Sotelo-Hitschfe, Tamara; Gutiérrez, Robin; Córdova, Andrés; Valdebenito, Rocío; Frommer, Wolf B.; Barros, L. Felipe

doi:10.3389/fnene.2010.00026

Cited by 133 publications

(145 citation statements)

References 40 publications

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“…As shown in Fig. S1, exposure to physiological NH + 4 levels had no apparent effect on cytosolic glucose concentration nor on the rate of glucose consumption measured with a transport block protocol (29). We conclude that physiological NH + 4 does not stimulate glucose consumption in astrocytes.…”

Section: Resultsmentioning

confidence: 72%

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

Lerchundi

Fernández‐Moncada

Contreras-Baeza

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Neural activity is accompanied by a transient mismatch between local glucose and oxygen metabolism, a phenomenon of physiological and pathophysiological importance termed aerobic glycolysis. Previous studies have proposed glutamate and K + as the neuronal signals that trigger aerobic glycolysis in astrocytes. Here we used a panel of genetically encoded FRET sensors in vitro and in vivo to investigate the participation of NH + 4 , a by-product of catabolism that is also released by active neurons. Astrocytes in mixed cortical cultures responded to physiological levels of NH + 4 with an acute rise in cytosolic lactate followed by lactate release into the extracellular space, as detected by a lactate-sniffer. An acute increase in astrocytic lactate was also observed in acute hippocampal slices exposed to NH + 4 and in the somatosensory cortex of anesthetized mice in response to i.v. NH + 4 . Unexpectedly, NH + 4 had no effect on astrocytic glucose consumption. Parallel measurements showed simultaneous cytosolic pyruvate accumulation and NADH depletion, suggesting the involvement of mitochondria. An inhibitor-stop technique confirmed a strong inhibition of mitochondrial pyruvate uptake that can be explained by mitochondrial matrix acidification. These results show that physiological NH + 4 diverts the flux of pyruvate from mitochondria to lactate production and release. Considering that NH + 4 is produced stoichiometrically with glutamate during excitatory neurotransmission, we propose that NH + 4 behaves as an intercellular signal and that pyruvate shunting contributes to aerobic lactate production by astrocytes.B rain tissue is almost exclusively energized by the oxidation of glucose. However, during neuronal activation, there is a larger increase in local glucose consumption relative to oxygen consumption (1). As this mismatch occurs in the presence of normal or augmented oxygen levels, it has been termed aerobic glycolysis, paralleling the signal detected by functional magnetic resonance imaging (2). Aerobic glycolysis and its associated lactate surge are causally linked to diverse functions of the brain in health and disease (3-10). Two signals are known to trigger aerobic glycolysis in brain tissue: glutamate and K + , which are released by active neurons and stimulate glycolysis in astrocytes (11,12).Neurons produce as much NH + 4 as they produce glutamate, both molecules being stoichiometrically linked in the glutamateglutamine cycle (13). Brain tissue NH + 4 increases within seconds of neural activation (14-16) and is quickly released to the interstitium (17, 18) to be captured by astrocytes through K + channels and transporters (19). It is well established that chronic exposure to pathological levels of NH + 4 such as those observed during liver failure has a major impact on brain metabolism, but it is not known whether this molecule may affect energy metabolism at physiological levels, particularly within the time scale of synaptic transmission. A previous study showed a reversible rise in brain tissue la...

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Section: Resultsmentioning

confidence: 72%

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

Lerchundi

Fernández‐Moncada

Contreras-Baeza

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the barrier function of endfeet decreases under pathological conditions and may conceivably be a physiologically regulated variable (Nuriya et al 2013). Unlike muscle cells and adipocytes, astrocytes maintain a substantial pool of glucose (Bittner et al 2010(Bittner et al , 2011Prebil et al 2011;Ruminot et al 2011). Glucose may leave astrocytes at the perisynaptic processes via GLUT1, which by virtue of its relatively low affinity for glucose is similarly equipped to facilitate influx and efflux.…”

Section: Energy Uptake Storage and Deliverymentioning

confidence: 99%

The Astrocyte: Powerhouse and Recycling Center

Weber

Barros

2015

Cold Spring Harb Perspect Biol

157

121

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Brain metabolism is characterized by fuel monodependence, high-energy expenditure, autonomy from the rest of body, local recycling, and marked division of labor between cell types. Although neurons spend most of the brain's energy on signaling, astrocytes bear the brunt of the metabolic load, controlling the composition of the interstitial fluid, supplying neurons with energy substrates and precursors for biosynthesis, and recycling neurotransmitters, oxidized scavengers, and other waste products. Outstanding questions in this field are the role of oligodendrocytes, the metabolic behavior of the different subtypes of astrocytes during development and disease, and the emerging notion that metabolism may participate directly in information processing. T he energy requirements of the central nervous system (CNS) are very high compared with those of other organs. Although the brain accounts for merely 2% of body weight, it receives 15% of cardiac output, and uses 20% of the oxygen and 25% of the glucose of the total body turnover (Magistretti 2008). A special microarchitecture has evolved to support this extreme need, in which glial cells play a central role (Fig. 1). The microvasculature consists of a complex and dense network of highly interconnected blood vessels (Weber et al. 2008;Blinder et al. 2013) to ensure adequate delivery of oxygen and glucose. Although oxygen diffuses freely into the parenchyma, glucose and other hydrophilic energy substrates are translocated across membranes via specific transporter proteins (Fig. 1). The astrocyte is a polarized cell. One set of astrocytic processes ensheaths the vasculature and a second set reaches toward the synapse, the site of highest energy demand (Harris et al. 2012). Much of the ATP produced in the brain is spent by neurons on the recovery of ion gradients challenged by postsynaptic potentials, with a smaller investment in action potentials and neurotransmitter recycling (Harris et al. 2012). Astrocytes consume considerable energy for their own needs and the cycling of metabolically relevant substances for neurons. These metabolic processes in astrocytes and neurons are the basis for brain mapping using functional magnetic resonance imaging and positron emission tomography (PET)-methods that capture local metabolism either directly or indirectly via hemodynamic changes (Magistretti 2008;Belanger et al. 2011a). Levels of energy consumption in the whole brain are almost constant. However, individual neurons can increase their consumption dramatically. For example, a striatal neuron may Overview of astrocytic metabolism. (Inset) Astrocytes (green) reside between blood vessels (red) and neurons (yellow). Neurons and oligodendrocytes (blue) are not in direct contact with vessels. Astrocytes form metabolic domains and are coupled by gap junctions, through which they exchange metabolites and ions. Energy: The main energy substrate of the brain is glucose (glc), which crosses the endothelium and enters astrocytes via the glucose transporter GLUT1. Glucose is converted b...

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“…The uptake may involve glucose transporter GLUT4, the expression of which in astrocytes was recently confirmed with immunocytochemical staining (59). In the present study, we have addressed this question using a glucose nanosensor based on FRET, which allows high temporal resolution measurement of the dynamic glucose concentration in single cells (60).…”

mentioning

confidence: 99%

Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes

Muhič

Vardjan

Chowdhury

et al. 2015

Journal of Biological Chemistry

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Background: Astrocytes contain glycogen, an energy buffer in the brain. Results: Stimulation with insulin and IGF-1 decreases cytosolic glucose concentration in astrocytes without affecting glucose entry across the astrocyte plasma membrane. Conclusion: Insulin and IGF-1 boost the process of glycogen formation. Significance: This is the first high temporal resolution measurement of the decrease of glucose levels in astrocytes resulting from insulin and IGF-1 stimulation.

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High resolution measurement of the glycolytic rate

Cited by 133 publications

References 40 publications

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

The Astrocyte: Powerhouse and Recycling Center

Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes

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