Control of mitochondrial pH by uncoupling protein 4 in astrocytes promotes neuronal survival

Handle URI:
http://hdl.handle.net/10754/563762
Title:
Control of mitochondrial pH by uncoupling protein 4 in astrocytes promotes neuronal survival
Authors:
Lambert, Hélène Perreten; Zenger, Manuel; Azarias, Guillaume; Chatton, Jean Yves; Magistretti, Pierre J. ( 0000-0002-6678-320X ) ; Lengacher, Sylvain
Abstract:
Brain activity is energetically costly and requires a steady and highly regulated flow of energy equivalents between neural cells. It is believed that a substantial share of cerebral glucose, the major source of energy of the brain, will preferentially be metabolized in astrocytes via aerobic glycolysis. The aim of this study was to evaluate whether uncoupling proteins (UCPs), located in the inner membrane of mitochondria, play a role in setting up the metabolic response pattern of astrocytes. UCPs are believed to mediate the transmembrane transfer of protons, resulting in the uncoupling of oxidative phosphorylation from ATP production. UCPs are therefore potentially important regulators of energy fluxes. The main UCP isoforms expressed in the brain are UCP2, UCP4, and UCP5. We examined in particular the role of UCP4 in neuron-astrocyte metabolic coupling and measured a range of functional metabolic parameters including mitochondrial electrical potential and pH, reactive oxygen species production, NAD/NADH ratio, ATP/ADP ratio, CO2 and lactate production, and oxygen consumption rate. In brief, we found that UCP4 regulates the intramitochondrial pH of astrocytes, which acidifies as a consequence of glutamate uptake, with the main consequence of reducing efficiency of mitochondrial ATP production. The diminished ATP production is effectively compensated by enhancement of glycolysis. This nonoxidative production of energy is not associated with deleterious H2O2 production. We show that astrocytes expressing more UCP4 produced more lactate, which is used as an energy source by neurons, and had the ability to enhance neuronal survival.
KAUST Department:
Bioscience Program; Biological and Environmental Sciences and Engineering (BESE) Division
Publisher:
American Society for Biochemistry & Molecular Biology (ASBMB)
Journal:
Journal of Biological Chemistry
Issue Date:
18-Sep-2014
DOI:
10.1074/jbc.M114.570879
PubMed ID:
25237189
PubMed Central ID:
PMC4223307
Type:
Article
ISSN:
00219258
Sponsors:
This work was supported by Swiss National Science Foundation Grants 108336 (to P. J. M.) and 31003A-135720 (to J. Y. C.).
Additional Links:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223307
Appears in Collections:
Articles; Bioscience Program; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorLambert, Hélène Perretenen
dc.contributor.authorZenger, Manuelen
dc.contributor.authorAzarias, Guillaumeen
dc.contributor.authorChatton, Jean Yvesen
dc.contributor.authorMagistretti, Pierre J.en
dc.contributor.authorLengacher, Sylvainen
dc.date.accessioned2015-08-03T12:09:17Zen
dc.date.available2015-08-03T12:09:17Zen
dc.date.issued2014-09-18en
dc.identifier.issn00219258en
dc.identifier.pmid25237189en
dc.identifier.doi10.1074/jbc.M114.570879en
dc.identifier.urihttp://hdl.handle.net/10754/563762en
dc.description.abstractBrain activity is energetically costly and requires a steady and highly regulated flow of energy equivalents between neural cells. It is believed that a substantial share of cerebral glucose, the major source of energy of the brain, will preferentially be metabolized in astrocytes via aerobic glycolysis. The aim of this study was to evaluate whether uncoupling proteins (UCPs), located in the inner membrane of mitochondria, play a role in setting up the metabolic response pattern of astrocytes. UCPs are believed to mediate the transmembrane transfer of protons, resulting in the uncoupling of oxidative phosphorylation from ATP production. UCPs are therefore potentially important regulators of energy fluxes. The main UCP isoforms expressed in the brain are UCP2, UCP4, and UCP5. We examined in particular the role of UCP4 in neuron-astrocyte metabolic coupling and measured a range of functional metabolic parameters including mitochondrial electrical potential and pH, reactive oxygen species production, NAD/NADH ratio, ATP/ADP ratio, CO2 and lactate production, and oxygen consumption rate. In brief, we found that UCP4 regulates the intramitochondrial pH of astrocytes, which acidifies as a consequence of glutamate uptake, with the main consequence of reducing efficiency of mitochondrial ATP production. The diminished ATP production is effectively compensated by enhancement of glycolysis. This nonoxidative production of energy is not associated with deleterious H2O2 production. We show that astrocytes expressing more UCP4 produced more lactate, which is used as an energy source by neurons, and had the ability to enhance neuronal survival.en
dc.description.sponsorshipThis work was supported by Swiss National Science Foundation Grants 108336 (to P. J. M.) and 31003A-135720 (to J. Y. C.).en
dc.publisherAmerican Society for Biochemistry & Molecular Biology (ASBMB)en
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223307en
dc.titleControl of mitochondrial pH by uncoupling protein 4 in astrocytes promotes neuronal survivalen
dc.typeArticleen
dc.contributor.departmentBioscience Programen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalJournal of Biological Chemistryen
dc.identifier.pmcidPMC4223307en
dc.contributor.institutionSchool of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de LausanneLausanne, Switzerlanden
dc.contributor.institutionDepartment of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9Lausanne, Switzerlanden
dc.contributor.institutionCenter for Psychiatric NeurosciencePrilly-Lausanne, Switzerlanden
kaust.authorMagistretti, Pierre J.en

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