The oxidized form of vitamin C, dehydroascorbic acid, regulates neuronal energy metabolism

Authors

  • Pedro Cisternas,

    1. Laboratorio de Neurobiología, Departamento de Biología Celular, Centro de Microscopía Avanzada CMA BIOBIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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  • Carmen Silva-Alvarez,

    1. Laboratorio de Neurobiología, Departamento de Biología Celular, Centro de Microscopía Avanzada CMA BIOBIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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  • Fernando Martínez,

    1. Laboratorio de Neurobiología, Departamento de Biología Celular, Centro de Microscopía Avanzada CMA BIOBIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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  • Emilio Fernandez,

    1. Institute of Functional Biology and Genomics, Department of Biochemistry and Molecular Biology, University of Salamanca-CSIC, Salamanca, Spain
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  • Luciano Ferrada,

    1. Laboratorio de Neurobiología, Departamento de Biología Celular, Centro de Microscopía Avanzada CMA BIOBIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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  • Karina Oyarce,

    1. Laboratorio de Neurobiología, Departamento de Biología Celular, Centro de Microscopía Avanzada CMA BIOBIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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  • Katterine Salazar,

    1. Laboratorio de Neurobiología, Departamento de Biología Celular, Centro de Microscopía Avanzada CMA BIOBIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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  • Juan P. Bolaños,

    Corresponding author
    1. Institute of Functional Biology and Genomics, Department of Biochemistry and Molecular Biology, University of Salamanca-CSIC, Salamanca, Spain
    • Address correspondence and reprint requests to Francisco Nualart, Laboratorio de Neurobiología, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Casilla 160 C, Concepción, Chile. E-mail: frnualart@udec.cl (or) Juan P. Bolaños, Institute of Functional Biology and Genomics, Department of Biochemistry and Molecular Biology, University of Salamanca-CSIC, Zacarias Gonzalez, 2, 37007 Salamanca, Spain. E-mail: jbolanos@usal.es

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    • These authors contributed equally to this work.
  • Francisco Nualart

    Corresponding author
    1. Laboratorio de Neurobiología, Departamento de Biología Celular, Centro de Microscopía Avanzada CMA BIOBIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
    • Address correspondence and reprint requests to Francisco Nualart, Laboratorio de Neurobiología, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Casilla 160 C, Concepción, Chile. E-mail: frnualart@udec.cl (or) Juan P. Bolaños, Institute of Functional Biology and Genomics, Department of Biochemistry and Molecular Biology, University of Salamanca-CSIC, Zacarias Gonzalez, 2, 37007 Salamanca, Spain. E-mail: jbolanos@usal.es

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    • These authors contributed equally to this work.

Abstract

Vitamin C is an essential factor for neuronal function and survival, existing in two redox states, ascorbic acid (AA), and its oxidized form, dehydroascorbic acid (DHA). Here, we show uptake of both AA and DHA by primary cultures of rat brain cortical neurons. Moreover, we show that most intracellular AA was rapidly oxidized to DHA. Intracellular DHA induced a rapid and dramatic decrease in reduced glutathione that was immediately followed by a spontaneous recovery. This transient decrease in glutathione oxidation was preceded by an increase in the rate of glucose oxidation through the pentose phosphate pathway (PPP), and a concomitant decrease in glucose oxidation through glycolysis. DHA stimulated the activity of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Furthermore, we found that DHA stimulated the rate of lactate uptake by neurons in a time- and dose-dependent manner. Thus, DHA is a novel modulator of neuronal energy metabolism by facilitating the utilization of glucose through the PPP for antioxidant purposes.

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We proposed that the ascorbic acid (AA) taken up by neurons is rapidly oxidized to dehydroascorbic acid (DHA), which inhibits glycolysis and activates the pentose phosphate pathway (PPP), consequently producing NADPH, a critical antioxidant in the recycling of oxidized glutathione (GSSG). In these metabolic conditions, neurons increase lactate uptake, probably using it as an energy source. This data supported the idea that DHA could play a critical role in the modulation of energy metabolism in neurons.

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