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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Detalhes bibliográficos
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, Lopez de Munain, Adolfo, Pardo Merino, Beatriz, Satrustegui Gil Delgado, Jorgina, Arco, Araceli del
Formato: artículo
Fecha de publicación:2022
País:España
Recursos:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/726900
Acesso em linha:https://hdl.handle.net/10486/726900
https://dx.doi.org/10.1523/JNEUROSCI.1463-21.2022
Access Level:acceso abierto
Palavra-chave:Aralar/AGC1/Slc25a12
calcium regulation
glycolysis
malate aspartate shuttle
mitochondrial calcium uniporter
neuronal metabolism
Biología y Biomedicina / Biología
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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, LauraLopez de Munain, AdolfoPardo Merino, BeatrizSatrustegui Gil Delgado, JorginaArco, Araceli delAralar/AGC1/Slc25a12calcium regulationglycolysismalate aspartate shuttlemitochondrial calcium uniporterneuronal metabolismBiología y Biomedicina / BiologíaCalcium 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 activationThis work was supported by Spanish Ministry of Science, Innovation and Universities SAF201456929R 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 Madrid. The qPCR experimental development was provided by the Genomics and NGS Core Facility at the CBMSOSociety for NeuroscienceFacultad de CienciasDepartamento de Biología MolecularAgencia Estatal de Investigación20222022-05-11research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10486/726900https://dx.doi.org/10.1523/JNEUROSCI.1463-21.202235387872reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7269002026-06-23T12:46:27Z
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
Biología y Biomedicina / Biología
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
Lopez de Munain, Adolfo
Pardo Merino, Beatriz
Satrustegui Gil Delgado, Jorgina
Arco, Araceli del
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
Lopez de Munain, Adolfo
Pardo Merino, Beatriz
Satrustegui Gil Delgado, Jorgina
Arco, Araceli del
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
Lopez de Munain, Adolfo
Pardo Merino, Beatriz
Satrustegui Gil Delgado, Jorgina
Arco, Araceli del
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Facultad de Ciencias
Departamento de Biología Molecular
Agencia Estatal de Investigación
dc.subject.none.fl_str_mv Aralar/AGC1/Slc25a12
calcium regulation
glycolysis
malate aspartate shuttle
mitochondrial calcium uniporter
neuronal metabolism
Biología y Biomedicina / Biología
topic Aralar/AGC1/Slc25a12
calcium regulation
glycolysis
malate aspartate shuttle
mitochondrial calcium uniporter
neuronal metabolism
Biología y Biomedicina / Biología
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
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-05-11
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10486/726900
https://dx.doi.org/10.1523/JNEUROSCI.1463-21.2022
35387872
url https://hdl.handle.net/10486/726900
https://dx.doi.org/10.1523/JNEUROSCI.1463-21.2022
identifier_str_mv 35387872
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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