title: Uncoupling Protein 2 (UCP2) Function in the Brain as Revealed by the Cerebral Metabolism of (1-13C)-Glucose.
abstract: The mitochondrial aspartate/glutamate transporter Aralar/AGC1/Slc25a12 is critically involved in brain aspartate synthesis, and AGC1 deficiency results in a drastic fall of brain aspartate levels in humans and mice. It has recently been described that the uncoupling protein UCP2 transports four carbon metabolites including aspartate. Since UCP2 is expressed in several brain cell types and AGC1 is mainly neuronal, we set to test whether UCP2 could be a mitochondrial aspartate carrier in the brain glial compartment. The study of the cerebral metabolism of (1-13C)-glucose in vivo in wild type and UCP2-knockout mice showed no differences in C3 or C2 labeling of aspartate, suggesting that UCP2 does not function as a mitochondrial aspartate carrier in brain. However, surprisingly, a clear decrease (of about 30-35 %) in the fractional enrichment of glutamate, glutamine and GABA was observed in the brains of UCP2-KO mice which was not associated with differences in either glucose or lactate enrichments. The results suggest that the dilution in the labeling of glutamate and its downstream metabolites could originate from the uptake of an unlabeled substrate that could not leave the matrix via UCP2 becoming trapped in the matrix. Understanding the nature of the unlabeled substrate and its precursor(s) as alternative substrates to glucose is of interest in the context of neurological diseases associated with UCP2.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM-Universidad Autónoma de Madrid, c/Nicolás Cabrera 1, 28049, Madrid, Spain.|CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.|Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, 28049, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Contreras
authors.affiliation: Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040, Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rial
authors.affiliation: Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Instituto de Investigaciones Biomédicas 'Alberto Sols' C.S.I.C./U.A.M., c/ Arturo Duperier 4, 28029, Madrid, Spain. scerdan@iib.uam.es.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Cerdan
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM-Universidad Autónoma de Madrid, c/Nicolás Cabrera 1, 28049, Madrid, Spain. jsatrustegui@cbm.csic.es.|CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain. jsatrustegui@cbm.csic.es.|Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, 28049, Madrid, Spain. jsatrustegui@cbm.csic.es.
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrustegui
mesh_terms: D000818:Animals; D002247:Carbon Isotopes / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071246:Uncoupling Protein 2 / Q000172:deficiency / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002247:Carbon Isotopes; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D005973:Glutamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005947:Glucose
keywords: (1–13C)-glucose; Aspartate; Cerebral metabolism; Mitochondria; UCP2