Astrocyte - neuron lactate shuttle may boost more ATP supply to the neuron under hypoxic conditions - in silico study supported by in vitro expression dataReportar como inadecuado




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BMC Systems Biology

, 5:162

Empirical systems biology

Abstract

BackgroundNeuro-glial interactions are important for normal functioning of the brain as well as brain energy metabolism. There are two major working models - in the classical view, both neurons and astrocytes can utilize glucose as the energy source through oxidative metabolism, whereas in the astrocyte-neuron lactate shuttle hypothesis ANLSH it is the astrocyte which can consume glucose through anaerobic glycolysis to pyruvate and then to lactate, and this lactate is secreted to the extracellular space to be taken up by the neuron for further oxidative degradation.

ResultsIn this computational study, we have included hypoxia-induced genetic regulation of these enzymes and transporters, and analyzed whether the ANLSH model can provide an advantage to either cell type in terms of supplying the energy demand. We have based this module on our own experimental analysis of hypoxia-dependent regulation of transcription of key metabolic enzymes. Using this experimentation-supported in silico modeling, we show that under both normoxic and hypoxic conditions in a given time period ANLSH model does indeed provide the neuron with more ATP than in the classical view.

ConclusionsAlthough the ANLSH is energetically more favorable for the neuron, it is not the case for the astrocyte in the long term. Considering the fact that astrocytes are more resilient to hypoxia, we would propose that there is likely a switch between the two models, based on the energy demand of the neuron, so as to maintain the survival of the neuron under hypoxic or glucose-and-oxygen-deprived conditions.

Abbreviationsxy: compartments

Glcglucose

GLUTglucose transporter

MCTlactate transporter

HKhexokinase

PFKphosphofructokinase

GAPDHglyceraldehyde-P-dehydrogenase

PKpyruvate kinase

LDHlactate dehydrogenase

AcoAAcetyl coenzyme A

a-KGalpha-ketoglutarate

SucCoAsuccinyl coenzyme A

Sucsuccinate

Malmalate

OxAcoxaloacetate

ATPadenosine triphosphate

NADHnicotinamide adenine dinucleotide

FADH2flavin adenine dinucleotide

GTPguanosine-5-triphosphate

ETCelectron transport chain

G6Pglucose-6-phosphate

GAPglyceraldehyde-3-phosphate

BPGbisphosphoglycerate

PHasepyrolyl hydroxylase

HIFhypoxia-inducible factor

Crcreatine

P-Crphospho-creatine

PDPassive-facilitated diffusion

MMMichaelis Menten

HMMHenri Michaelis Menten

UIUncompetitive inhibition

MAMass action

neuron

astrocyte

cytosol

nucleus

mitochondrion

blood used interchangibly with -capillary-

extracellular area

Electronic supplementary materialThe online version of this article doi:10.1186-1752-0509-5-162 contains supplementary material, which is available to authorized users.

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Autor: Seda Genc - Isil A Kurnaz - Mustafa Ozilgen

Fuente: https://link.springer.com/







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