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Cited by 146Neuroscience and Neuropharmacology ResearchRedox biology and oxidative stressCancer, Hypoxia, and Metabolism

The redox switch/redox coupling hypothesis

Cerdán, Sebastián, Rodrigues, Tiago B., Sierra, Alejandra, Benito, Marina, Fonseca, Luis L., Fonseca, Carla P., García-Martín, María L.·2006·Neurochemistry International
DOI 10.1016/j.neuint.2005.12.036
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Abstract

We provide an integrative interpretation of neuroglial metabolic coupling including the presence of subcellular compartmentation of pyruvate and monocarboxylate recycling through the plasma membrane of both neurons and glial cells. The subcellular compartmentation of pyruvate allows neurons and astrocytes to select between glucose and lactate as alternative substrates, depending on their relative extracellular concentration and the operation of a redox switch. This mechanism is based on the inhibition of glycolysis at the level of glyceraldehyde 3-phosphate dehydrogenase by NAD(+) limitation, under sufficiently reduced cytosolic NAD(+)/NADH redox conditions. Lactate and pyruvate recycling through the plasma membrane allows the return to the extracellular medium of cytosolic monocarboxylates enabling their transcellular, reversible, exchange between neurons and astrocytes. Together, intracellular pyruvate compartmentation and monocarboxylate recycling result in an effective transcellular coupling between the cytosolic NAD(+)/NADH redox states of both neurons and glial cells. Following glutamatergic neurotransmission, increased glutamate uptake by the astrocytes is proposed to augment glycolysis and tricarboxylic acid cycle activity, balancing to a reduced cytosolic NAD(+)/NADH in the glia. Reducing equivalents are transferred then to the neuron resulting in a reduced neuronal NAD(+)/NADH redox state. This may eventually switch off neuronal glycolysis, favoring the oxidation of extracellular lactate in the lactate dehydrogenase (LDH) equilibrium and in the neuronal tricarboxylic acid cycles. Finally, pyruvate derived from neuronal lactate oxidation, may return to the extracellular space and to the astrocyte, restoring the basal redox state and beginning a new loop of the lactate/pyruvate transcellular coupling cycle. Transcellular redox coupling operates through the plasma membrane transporters of monocarboxylates, similarly to the intracellular redox shuttles coupling the cytosolic and mitochondrial redox states through the transporters of the inner mitochondrial membrane. Finally, transcellular redox coupling mechanisms may couple glycolytic and oxidative zones in other heterogeneous tissues including muscle and tumors.

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  • The difference in resting NADHCYT makes some baseline redox exchange likely between the two compartments.

    “The difference in resting NADHCYT makes some baseline redox exchange likely between the two compartments (Cerdán et al., 2006); even with equal total (lactate + pyruvate) levels in the two cell types, astrocytic lactate could exchange for neuronal pyruvate, effectively allowing transfer of the glycolysis-derived NADH reducing equivalents from astrocytes to neurons.”

    From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Cerdán et al., 2006

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Authors
Cerdán, S., Rodrigues, T. B., Sierra, A., Benito, M., Fonseca, L. L., Fonseca, C. P., & García-Martín, M. L.
Affiliations
  • Instituto de Investigaciones Biomédicas Sols-Morreale (ES)
  • Centro de Neurociências e Biologia Celular (PT)
ORCID
Venue
Neurochemistry International
Publisher
Elsevier BV
Published
2006-05
Volume
48
Issue
6-7
Pages
523-530
ISSN
0197-0186 (ISSN-L)
DOI
10.1016/j.neuint.2005.12.036
OpenAlex
W2128632634
Cited by
146
References
59
Citations by year
2025: 2 · 2024: 3 · 2023: 8 · 2022: 1 · 2021: 4 · 2020: 6 · 2019: 2 · 2018: 9 · 2017: 6 · 2016: 3 · 2015: 8 · 2014: 9 · 2013: 12 · 2012: 9
FWCI
1.34
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Neurochemistry International (publishedVersion)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
Funders
  • Ministerio de Educación, Cultura y Deporte (C03/10, C03/155, FISss C03/08, PI051530, PI051845)
  • Instituto de Salud Carlos III
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
redox coupling, lactate, NAD+/NADH redox state, glycolysis inhibition, glyceraldehyde-3-phosphate dehydrogenase, astrocytes, neurons, glutamate uptake, glutamatergic neurotransmission, lactate dehydrogenase, TCA cycle, monocarboxylate transporters, plasma membrane, redox shuttle
MeSH terms
Animals, Astrocytes, Biological Transport, Active, Cell Membrane, Glucose, Glycolysis, Humans, L-Lactate Dehydrogenase, NAD, Neuroglia, Neurons, Oxidation-Reduction, Pyruvic Acid, Lactic Acid, Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+), Monocarboxylic Acid Transporters

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