A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation

Calcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In embryonic mouse cortical neurons using glucose as only fuel, activation by NMDA elicits a strong workload (ATP demand)-dependent on Na+ and Ca2+ entry, and stimulates glu...

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Autores: Pérez-Liébana, Irene, Juaristi, Inés, González-Sánchez, Paloma, González-Moreno, Luis, Rial, Eduardo, Podunavac, Maša, Zakarian, Armen, Molgó, Jordi, Vallejo-Illarramendi, Ainara, Mosqueira-Martín, Laura, López de Munain, Adolfo, Pardo, Beatriz, Satrústegui, Jorgina, Del Arco, Araceli
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/367104
Acceso en línea:http://hdl.handle.net/10261/367104
Access Level:acceso abierto
Palabra clave:Aralar/AGC1/Slc25a12
calcium regulation
glycolysis
malate aspartate shuttle
mitochondrial calcium uniporter
neuronal metabolism.
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oai_identifier_str oai:digital.csic.es:10261/367104
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation
title A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation
spellingShingle A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation
Pérez-Liébana, Irene
Aralar/AGC1/Slc25a12
calcium regulation
glycolysis
malate aspartate shuttle
mitochondrial calcium uniporter
neuronal metabolism.
title_short A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation
title_full A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation
title_fullStr A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation
title_full_unstemmed A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation
title_sort A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation
dc.creator.none.fl_str_mv Pérez-Liébana, Irene
Juaristi, Inés
González-Sánchez, Paloma
González-Moreno, Luis
Rial, Eduardo
Podunavac, Maša
Zakarian, Armen
Molgó, Jordi
Vallejo-Illarramendi, Ainara
Mosqueira-Martín, Laura
López de Munain, Adolfo
Pardo, Beatriz
Satrústegui, Jorgina
Del Arco, Araceli
author Pérez-Liébana, Irene
author_facet Pérez-Liébana, Irene
Juaristi, Inés
González-Sánchez, Paloma
González-Moreno, Luis
Rial, Eduardo
Podunavac, Maša
Zakarian, Armen
Molgó, Jordi
Vallejo-Illarramendi, Ainara
Mosqueira-Martín, Laura
López de Munain, Adolfo
Pardo, Beatriz
Satrústegui, Jorgina
Del Arco, Araceli
author_role author
author2 Juaristi, Inés
González-Sánchez, Paloma
González-Moreno, Luis
Rial, Eduardo
Podunavac, Maša
Zakarian, Armen
Molgó, Jordi
Vallejo-Illarramendi, Ainara
Mosqueira-Martín, Laura
López de Munain, Adolfo
Pardo, Beatriz
Satrústegui, Jorgina
Del Arco, Araceli
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Fundación Ramón Areces
Ministerio de Economía y Competitividad (España)
Comunidad de Madrid
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Aralar/AGC1/Slc25a12
calcium regulation
glycolysis
malate aspartate shuttle
mitochondrial calcium uniporter
neuronal metabolism.
topic Aralar/AGC1/Slc25a12
calcium regulation
glycolysis
malate aspartate shuttle
mitochondrial calcium uniporter
neuronal metabolism.
description Calcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In embryonic mouse cortical neurons using glucose as only fuel, activation by NMDA elicits a strong workload (ATP demand)-dependent on Na+ and Ca2+ entry, and stimulates glucose uptake, glycolysis, pyruvate and lactate production, and oxidative phosphorylation (OXPHOS) in a Ca2+-dependent way. We find that Ca2+ upregulation of glycolysis, pyruvate levels, and respiration, but not glucose uptake, all depend on Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier, component of the malate-aspartate shuttle (MAS). MAS activation increases glycolysis, pyruvate production, and respiration, a process inhibited in the presence of BAPTA-AM, suggesting that the Ca2+ binding motifs in Aralar may be involved in the activation. Mitochondrial calcium uniporter (MCU) silencing had no effect, indicating that none of these processes required MCU-dependent mitochondrial Ca2+ uptake. The neuronal respiratory response to carbachol was also dependent on Aralar, but not on MCU. We find that mouse cortical neurons are endowed with a constitutive ER-to-mitochondria Ca2+ flow maintaining basal cell bioenergetics in which ryanodine receptors, RyR2, rather than InsP3R, are responsible for Ca2+ release, and in which MCU does not participate. The results reveal that, in neurons using glucose, MCU does not participate in OXPHOS regulation under basal or stimulated conditions, while Aralar-MAS appears as the major Ca2+-dependent pathway tuning simultaneously glycolysis and OXPHOS to neuronal activation.SIGNIFICANCE STATEMENT Neuronal activation increases cell workload to restore ion gradients altered by activation. Ca2+ is involved in matching increased workload with ATP production, but the mechanisms are still unknown. We find that glycolysis, pyruvate production, and neuronal respiration are stimulated on neuronal activation in a Ca2+-dependent way, independently of effects of Ca2+ as workload inducer. Mitochondrial calcium uniporter (MCU) does not play a relevant role in Ca2+ stimulated pyruvate production and oxygen consumption as both are unchanged in MCU silenced neurons. However, Ca2+ stimulation is blunt in the absence of Aralar, a Ca2+-binding mitochondrial carrier component of Malate-Aspartate Shuttle (MAS). The results suggest that Ca2+-regulated Aralar-MAS activation upregulates glycolysis and pyruvate production, which fuels mitochondrial respiration, through regulation of cytosolic NAD+/NADH ratio.
publishDate 2022
dc.date.none.fl_str_mv 2022
2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/367104
url http://hdl.handle.net/10261/367104
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//SAF2014-56929-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-82560-R
http://dx.doi.org/10.1523/JNEUROSCI.1463-21.2022
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal StimulationPérez-Liébana, IreneJuaristi, InésGonzález-Sánchez, PalomaGonzález-Moreno, LuisRial, EduardoPodunavac, MašaZakarian, ArmenMolgó, JordiVallejo-Illarramendi, AinaraMosqueira-Martín, LauraLópez de Munain, AdolfoPardo, BeatrizSatrústegui, JorginaDel Arco, AraceliAralar/AGC1/Slc25a12calcium regulationglycolysismalate aspartate shuttlemitochondrial calcium uniporterneuronal metabolism.Calcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In embryonic mouse cortical neurons using glucose as only fuel, activation by NMDA elicits a strong workload (ATP demand)-dependent on Na+ and Ca2+ entry, and stimulates glucose uptake, glycolysis, pyruvate and lactate production, and oxidative phosphorylation (OXPHOS) in a Ca2+-dependent way. We find that Ca2+ upregulation of glycolysis, pyruvate levels, and respiration, but not glucose uptake, all depend on Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier, component of the malate-aspartate shuttle (MAS). MAS activation increases glycolysis, pyruvate production, and respiration, a process inhibited in the presence of BAPTA-AM, suggesting that the Ca2+ binding motifs in Aralar may be involved in the activation. Mitochondrial calcium uniporter (MCU) silencing had no effect, indicating that none of these processes required MCU-dependent mitochondrial Ca2+ uptake. The neuronal respiratory response to carbachol was also dependent on Aralar, but not on MCU. We find that mouse cortical neurons are endowed with a constitutive ER-to-mitochondria Ca2+ flow maintaining basal cell bioenergetics in which ryanodine receptors, RyR2, rather than InsP3R, are responsible for Ca2+ release, and in which MCU does not participate. The results reveal that, in neurons using glucose, MCU does not participate in OXPHOS regulation under basal or stimulated conditions, while Aralar-MAS appears as the major Ca2+-dependent pathway tuning simultaneously glycolysis and OXPHOS to neuronal activation.SIGNIFICANCE STATEMENT Neuronal activation increases cell workload to restore ion gradients altered by activation. Ca2+ is involved in matching increased workload with ATP production, but the mechanisms are still unknown. We find that glycolysis, pyruvate production, and neuronal respiration are stimulated on neuronal activation in a Ca2+-dependent way, independently of effects of Ca2+ as workload inducer. Mitochondrial calcium uniporter (MCU) does not play a relevant role in Ca2+ stimulated pyruvate production and oxygen consumption as both are unchanged in MCU silenced neurons. However, Ca2+ stimulation is blunt in the absence of Aralar, a Ca2+-binding mitochondrial carrier component of Malate-Aspartate Shuttle (MAS). The results suggest that Ca2+-regulated Aralar-MAS activation upregulates glycolysis and pyruvate production, which fuels mitochondrial respiration, through regulation of cytosolic NAD+/NADH ratio.This work was supported by Spanish Ministry of Science, Innovation and Universities SAF2014-56929R to J.S. and B.P.; SAF2017-82560-R to A.d.A. and B.P.; Fundación Ramón Areces to J.S.; and Fundación Ramón Areces institutional grant to Centro de Biología Molecular Severo Ochoa (CBMSO). I.P.-L. and L.G.-M. received predoctoral fellowships from MINECO. P.G.-S. received a postdoctoral research contract from Comunidad de MadridSociety for NeuroscienceMinisterio de Ciencia, Innovación y Universidades (España)Fundación Ramón ArecesMinisterio de Economía y Competitividad (España)Comunidad de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420222024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/367104reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//SAF2014-56929-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-82560-Rhttp://dx.doi.org/10.1523/JNEUROSCI.1463-21.2022Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3671042026-05-22T06:33:51Z
score 15,812429

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