Ignacio Fernández‐Moncada

Neurocentre Magendie

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L. Felipe Barros

Centro de Estudios Científicos

Iván Ruminot

Centro de Estudios Científicos

Giovanni Marsicano

Neurocentre Magendie

Karin Alegría

Centro de Estudios Científicos

Tamara Sotelo-Hitschfeld

Max Planck Institute for Metabolism Research

Rodrigo Lerchundi

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

Alejandro San Martín

Centro de Estudios Científicos

Felipe Baeza‐Lehnert

Leipzig University

Vinciane Saint‐Criq

Département Alimentation Humaine

Amber R. Philp

Austral University of Chile

Cooperative Institutions

Université de Bordeaux

Inserm

Centre National de la Recherche Scientifique

Neurocentre Magendie

Centro de Estudios Científicos

Austral University of Chile

Institut de Biochimie et Génétique Cellulaires

University of the Basque Country

Bordeaux Population Health

San Sebastián University

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Channel-Mediated Lactate Release by K⁺-Stimulated Astrocytes

Journal of Neuroscience (2015)

Tamara Sotelo-Hitschfeld Marı́a Isabel Niemeyer Philipp Mächler Iván Ruminot Rodrigo Lerchundi

Excitatory synaptic transmission is accompanied by a local surge in interstitial lactate that occurs despite adequate oxygen availability, a puzzling phenomenon termed aerobic glycolysis. In addition to its role as an energy substrate, recent studies have shown that lactate modulates neuronal excitability acting through various targets, including NMDA receptors and G-protein-coupled receptors specific for lactate, but little is known about the cellular and molecular mechanisms responsible for the increase in interstitial lactate. Using a panel of genetically encoded fluorescence nanosensors for energy metabolites, we show here that mouse astrocytes in culture, in cortical slices, and in vivo maintain a steady-state reservoir of lactate. The reservoir was released to the extracellular space immediately after exposure of astrocytes to a physiological rise in extracellular K + or cell depolarization. Cell-attached patch-clamp analysis of cultured astrocytes revealed a 37 pS lactate-permeable ion channel activated by cell depolarization. The channel was modulated by lactate itself, resulting in a positive feedback loop for lactate release. A rapid fall in intracellular lactate levels was also observed in cortical astrocytes of anesthetized mice in response to local field stimulation. The existence of an astrocytic lactate reservoir and its quick mobilization via an ion channel in response to a neuronal cue provides fresh support to lactate roles in neuronal fueling and in gliotransmission.

10.1523/jneurosci.5036-14.2015

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Citations (167)

Astroglial CB1 receptors, energy metabolism, and gliotransmission: an integrated signaling system?

Essays in Biochemistry (2023)

Ignacio Fernández‐Moncada Giovanni Marsicano

Astrocytes are key players in brain homeostasis and function. During the last years, several studies have cemented this notion by showing that these cells respond to neuronal signals and, via the release of molecules that modulate and support synaptic activity (gliotransmission) participates in the functions of the so-called tripartite synapse. Thus, besides their established control of brain metabolism, astrocytes can also actively control synaptic activity and behavior. Among the signaling pathways that shape the functions of astrocyte, the cannabinoid type-1 (CB1) receptor is emerging as a critical player in the control of both gliotransmission and the metabolic cooperation between astrocytes and neurons. In the present short review, we describe known and newly discovered properties of the astroglial CB1 receptors and their role in modulating brain function and behavior. Based on this evidence, we finally discuss how the functions and mode of actions of astrocyte CB1 receptors might represent a clear example of the inextricable relationship between energy metabolism and gliotransmission. These tight interactions will need to be taken into account for future research in astrocyte functions and call for a reinforcement of the theoretical and experimental bridges between studies on metabolic and synaptic functions of astrocytes.

Premovement neuronal activity

10.1042/ebc20220089

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Citations (11)

Non-preferential fuelling of the Na+/K+-ATPase pump

Biochemical Journal (2014)

Ignacio Fernández‐Moncada L. Felipe Barros

There is abundant evidence that glycolysis and the Na(+)/K(+)-ATPase pump are functionally coupled, and it is thought that the nature of the coupling is energetic, with glycolysis providing the ATP that fuels the pump. This notion has been instrumental to current models of brain energy metabolism. However, structural and biophysical considerations suggest that the pump should also have access to mitochondrial ATP, which is much more abundant. In the present study, we have investigated the source of ATP that fuels the Na(+) pump in astrocytes, taking advantage of the high temporal resolution of recently available FRET nanosensors for glucose, lactate and ATP. The activity of the Na(+) pump was assessed in parallel with the Na(+)-sensitive dye SBFI AM (Na(+)-binding benzofuran isophthalate acetoxymethyl ester). OXPHOS (oxidative phosphorylation) inhibition resulted in bulk ATP depletion and a 5-fold stimulation of glycolytic flux, in spite of which Na(+) pumping was inhibited by 90%. Mathematical modelling of ATP dynamics showed that the observed pump failure is inconsistent with preferential fuelling of the Na(+) pump by glycolytic ATP. We conclude that the nature of the functional coupling between the Na(+) pump and the glycolytic machinery is not energetic and that the pump is mainly fuelled by mitochondrial ATP.

Chemiosmosis

Adenosine triphosphate

Calcium pump

10.1042/bj20140003

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Citations (38)

Inhibition of the sodium-dependent HCO₃^- transporter SLC4A4, produces a cystic fibrosis-like airway disease phenotype

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Vinciane Saint‐Criq Anita Guequén Amber R. Philp Sandra Villanueva Tábata Apablaza

ABSTRACT Bicarbonate secretion is a fundamental process involved in maintaining acid-base homeostasis. Disruption of bicarbonate entry into airway lumen, as has been observed in cystic fibrosis, produces several defects in lung function due to thick mucus accumulation. Bicarbonate is critical for correct mucin deployment and there is increasing interest in understanding its role in airway physiology, particularly in the initiation of lung disease in children affected by cystic fibrosis, in the absence of detectable bacterial infection. The current model of anion secretion in mammalian airways consists of CFTR and TMEM16A as apical anion exit channels, with limited capacity for bicarbonate transport compared to chloride. However, both channels can couple to SLC26A4 anion exchanger to maximise bicarbonate secretion. Nevertheless, current models lack any details about the identity of the basolateral protein(s) responsible for bicarbonate uptake into airway epithelial cells. We report herein that the electrogenic, sodium-dependent, bicarbonate cotransporter, SLC4A4, is expressed in the basolateral membrane of human and mouse airways, and that it’s pharmacological inhibition or genetic silencing reduces bicarbonate secretion. In fully differentiated primary human airway cells, SLC4A4 inhibition induced an acidification of the airways surface liquid and markedly reduced the capacity of cells to recover from an acid load. Studies in the Slc4a4 -null mice revealed a previously unreported lung phenotype, characterized by mucus accumulation and reduced mucociliary clearance. Collectively, our results demonstrate that the reduction of SLC4A4 function induced a CF-like phenotype, even when chloride secretion remained intact, highlighting the important role SLC4A4 plays in bicarbonate secretion and mammalian airway function.

Bicarbonate

Mucociliary clearance

10.1101/2021.12.14.472535

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Bidirectional astrocytic GLUT1 activation by elevated extracellular K⁺

Glia (2020)

Ignacio Fernández‐Moncada Daniel Robles-Maldonado Pablo A. Castro Karin Alegría Robert Epp

Abstract The acute rise in interstitial K + that accompanies neural activity couples the energy demand of neurons to the metabolism of astrocytes. The effects of elevated K + on astrocytes include activation of aerobic glycolysis, inhibition of mitochondrial respiration and the release of lactate. Using a genetically encoded FRET glucose sensor and a novel protocol based on 3‐ O ‐methylglucose trans‐acceleration and numerical simulation of glucose dynamics, we report that extracellular K + is also a potent and reversible modulator of the astrocytic glucose transporter GLUT1. In cultured mouse astrocytes, the stimulatory effect developed within seconds, engaged both the influx and efflux modes of the transporter, and was detected even at 1 mM incremental K + . The modulation of GLUT1 explains how astrocytes are able to maintain their glucose pool in the face of strong glycolysis stimulation. We propose that the stimulation of GLUT1 by K + supports the production of lactate by astrocytes and the timely delivery of glucose to active neurons.

Neuroglia

Monocarboxylate transporter

Cellular respiration

10.1002/glia.23944

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Citations (16)

Near‐critical GLUT1 and Neurodegeneration

Journal of Neuroscience Research (2017)

L. Felipe Barros Alejandro San Martín Iván Ruminot Pamela Y. Sandoval Ignacio Fernández‐Moncada

Recent articles have drawn renewed attention to the housekeeping glucose transporter GLUT1 and its possible involvement in neurodegenerative diseases. Here we provide an updated analysis of brain glucose transport and the cellular mechanisms involved in its acute modulation during synaptic activity. We discuss how the architecture of the blood‐brain barrier and the low concentration of glucose within neurons combine to make endothelial/glial GLUT1 the master controller of neuronal glucose utilization, while the regulatory role of the neuronal glucose transporter GLUT3 emerges as secondary. The near‐critical condition of glucose dynamics in the brain suggests that subtle deficits in GLUT1 function or its activity‐dependent control by neurons may contribute to neurodegeneration. © 2017 Wiley Periodicals, Inc.

GLUT3

10.1002/jnr.23998

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Citations (41)

Targeting of astrocytic glucose metabolism by beta-hydroxybutyrate

Journal of Cerebral Blood Flow & Metabolism (2015)

Rocío Valdebenito Iván Ruminot Pamela Garrido-Gerter Ignacio Fernández‐Moncada Linda S. Forero-Quintero

The effectiveness of ketogenic diets and intermittent fasting against neurological disorders has brought interest to the effects of ketone bodies on brain cells. These compounds are known to modify the metabolism of neurons, but little is known about their effect on astrocytes, cells that control the supply of glucose to neurons and also modulate neuronal excitability through the glycolytic production of lactate. Here we have used genetically-encoded Förster Resonance Energy Transfer nanosensors for glucose, pyruvate and ATP to characterize astrocytic energy metabolism at cellular resolution. Our results show that the ketone body beta-hydroxybutyrate strongly inhibited astrocytic glucose consumption in mouse astrocytes in mixed cultures, in organotypic hippocampal slices and in acute hippocampal slices prepared from ketotic mice, while blunting the stimulation of glycolysis by physiological and pathophysiological stimuli. The inhibition of glycolysis was paralleled by an increased ability of astrocytic mitochondria to metabolize pyruvate. These results support the emerging notion that astrocytes contribute to the neuroprotective effect of ketone bodies.

Ketogenic Diet

Carbohydrate Metabolism

Anaerobic glycolysis

Neuroglia

10.1177/0271678x15613955

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Citations (59)

Inhibition of the sodium-dependent HCO3- transporter SLC4A4, produces a cystic fibrosis-like airway disease phenotype

eLife (2022)

Vinciane Saint‐Criq Anita Guequén Amber R. Philp Sandra Villanueva Tábata Apablaza

Bicarbonate secretion is a fundamental process involved in maintaining acid-base homeostasis. Disruption of bicarbonate entry into airway lumen, as has been observed in cystic fibrosis, produces several defects in lung function due to thick mucus accumulation. Bicarbonate is critical for correct mucin deployment and there is increasing interest in understanding its role in airway physiology, particularly in the initiation of lung disease in children affected by cystic fibrosis, in the absence of detectable bacterial infection. The current model of anion secretion in mammalian airways consists of CFTR and TMEM16A as apical anion exit channels, with limited capacity for bicarbonate transport compared to chloride. However, both channels can couple to SLC26A4 anion exchanger to maximise bicarbonate secretion. Nevertheless, current models lack any details about the identity of the basolateral protein(s) responsible for bicarbonate uptake into airway epithelial cells. We report herein that the electrogenic, sodium-dependent, bicarbonate cotransporter, SLC4A4, is expressed in the basolateral membrane of human and mouse airways, and that it’s pharmacological inhibition or genetic silencing reduces bicarbonate secretion. In fully differentiated primary human airway cells cultures, SLC4A4 inhibition induced an acidification of the airways surface liquid and markedly reduced the capacity of cells to recover from an acid load. Studies in the Slc4a4 -null mice revealed a previously unreported lung phenotype, characterized by mucus accumulation and reduced mucociliary clearance. Collectively, our results demonstrate that the reduction of SLC4A4 function induced a CF-like phenotype, even when chloride secretion remained intact, highlighting the important role SLC4A4 plays in bicarbonate secretion and mammalian airway function.

Bicarbonate

Mucociliary clearance

10.7554/elife.75871

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Citations (11)

Single-cell imaging tools for brain energy metabolism: a review

Neurophotonics (2014)

Alejandro San Martín Tamara Sotelo-Hitschfeld Rodrigo Lerchundi Ignacio Fernández‐Moncada Sebastián Ceballo

Neurophotonics comes to light at a time in which advances in microscopy and improved calcium reporters are paving the way toward high-resolution functional mapping of the brain. This review relates to a parallel revolution in metabolism. We argue that metabolism needs to be approached both in vitro and in vivo, and that it does not just exist as a low-level platform but is also a relevant player in information processing. In recent years, genetically encoded fluorescent nanosensors have been introduced to measure glucose, glutamate, ATP, NADH, lactate, and pyruvate in mammalian cells. Reporting relative metabolite levels, absolute concentrations, and metabolic fluxes, these sensors are instrumental for the discovery of new molecular mechanisms. Sensors continue to be developed, which together with a continued improvement in protein expression strategies and new imaging technologies, herald an exciting era of high-resolution characterization of metabolism in the brain and other organs.

Intermediary Metabolism

Cellular metabolism

10.1117/1.nph.1.1.011004

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Citations (57)

An enquiry to the role of CB1 receptors in neurodegeneration

Neurobiology of Disease (2023)

Ignacio Fernández‐Moncada Abel Eraso‐Pichot Tommaso Dalla Tor Bérénice Fortunato-Marsol Giovanni Marsicano

Neurodegenerative disorders are debilitating conditions that impair patient quality of life and that represent heavy social-economic burdens to society. Whereas the root of some of these brain illnesses lies in autosomal inheritance, the origin of most of these neuropathologies is scantly understood. Similarly, the cellular and molecular substrates explaining the progressive loss of brain functions remains to be fully described too. Indeed, the study of brain neurodegeneration has resulted in a complex picture, composed of a myriad of altered processes that include broken brain bioenergetics, widespread neuroinflammation and aberrant activity of signaling pathways. In this context, several lines of research have shown that the endocannabinoid system (ECS) and its main signaling hub, the type-1 cannabinoid (CB1) receptor are altered in diverse neurodegenerative disorders. However, some of these data are conflictive or poorly described. In this review, we summarize the findings about the alterations in ECS and CB1 receptors signaling in three representative brain illnesses, the Alzheimer's, Parkinson's and Huntington's diseases, and we discuss the relevance of these studies in understanding neurodegeneration development and progression, with a special focus on astrocyte function. Noteworthy, the analysis of ECS defects in neurodegeneration warrant much more studies, as our conceptual understanding of ECS function has evolved quickly in the last years, which now include glia cells and the subcellular-specific CB1 receptors signaling as critical players of brain functions.

10.1016/j.nbd.2023.106235

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Citations (6)