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Uncoupling Protein 2 (UCP2) Function in the Brain as Revealed by the Cerebral Metabolism of (1–13C)-Glucose

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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.

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Acknowledgments

The authors thank Barbara Sesé, Isabel Manso and María José Guillén for excellent technical support. This work was supported by Grants S2010/BMD-2402 and SAF2014-56929R to JS, S2010/BMD-2349 and SAF2014-57739-R to SC, and S2010/BMD-2402 and CSD2007-00020 to ER; and an institutional grant from Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa. LC has been the recipient of a Junta de Ampliación de Estudios-Consejo Superior de Investigaciones Científicas and CIBERER postdoctoral contracts. The authors declare no competing financial interests.

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Authors and Affiliations

  1. Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM-Universidad Autónoma de Madrid, c/Nicolás Cabrera 1, 28049, Madrid, Spain

    Laura Contreras & Jorgina Satrustegui

  2. CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain

    Laura Contreras & Jorgina Satrustegui

  3. Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, 28049, Madrid, Spain

    Laura Contreras & Jorgina Satrustegui

  4. Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040, Madrid, Spain

    Eduardo Rial

  5. 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

    Sebastian Cerdan

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  1. Laura Contreras
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  2. Eduardo Rial
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  3. Sebastian Cerdan
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  4. Jorgina Satrustegui
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Correspondence to Sebastian Cerdan or Jorgina Satrustegui.

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Especial Issue: Tribute to Mary C McKenna.

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Contreras, L., Rial, E., Cerdan, S. et al. Uncoupling Protein 2 (UCP2) Function in the Brain as Revealed by the Cerebral Metabolism of (1–13C)-Glucose. Neurochem Res 42, 108–114 (2017). https://doi.org/10.1007/s11064-016-1999-5

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