title: Control of mitochondrial pH by uncoupling protein 4 in astrocytes promotes neuronal survival.
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.
authors.affiliation: From the School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Hélène
authors.initials: H
authors.lastname: Perreten Lambert
authors.affiliation: From the School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Zenger
authors.affiliation: the Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland, and.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Azarias
authors.affiliation: the Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland, and.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Chatton
authors.affiliation: From the School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland, the King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia, the Center for Psychiatric Neuroscience, 1008 Prilly-Lausanne, Switzerland.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Magistretti
authors.affiliation: From the School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland, the Center for Psychiatric Neuroscience, 1008 Prilly-Lausanne, Switzerland Sylvain.Lengacher@epfl.ch.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lengacher
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D002245:Carbon Dioxide / Q000737:chemistry; D002470:Cell Survival; D018920:Coculture Techniques; D005452:Fluoresceins / Q000737:chemistry; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007773:Lactates / Q000737:chemistry; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D000071245:Mitochondrial Uncoupling Proteins; D009474:Neurons / Q000166:cytology*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption
chemical_list: D005452:Fluoresceins; D007773:Lactates; D026901:Membrane Transport Proteins; D000071245:Mitochondrial Uncoupling Proteins; C547516:Slc25a27 protein, mouse; D002245:Carbon Dioxide; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D005947:Glucose; C007740:fluorexon
keywords: Astrocyte; Glycolysis; Lactate; Mitochondria; Uncoupling Protein; pH Regulation