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Article Dans Une Revue Nature Metabolism Année : 2023

Weak neuronal glycolysis sustains cognition and organismal fitness

Résumé

The energy cost of neuronal activity is mainly sustained by glucose1,2. However, in an apparent paradox, neurons modestly metabolize glucose through glycolysis3-6, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase-fructose-2,6-bisphosphatase-3 (PFKFB3)3,7,8, a key glycolysis-promoting enzyme. To evaluate the in vivo physiological importance of this hypoglycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression. In vivo molecular, biochemical and metabolic flux analyses of these neurons revealed an accumulation of anomalous mitochondria, complex I disassembly, bioenergetic deficiency and mitochondrial redox stress. Notably, glycolysis-mediated nicotinamide adenine dinucleotide (NAD+) reduction impaired sirtuin-dependent autophagy. Furthermore, these mice displayed cognitive decline and a metabolic syndrome that was mimicked by confining Pfkfb3 expression to hypothalamic neurons. Neuron-specific genetic ablation of mitochondrial redox stress or brain NAD+ restoration corrected these behavioural alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions.

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Dates et versions

hal-04224688 , version 1 (02-10-2023)

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Daniel Jimenez-Blasco, Jesús Agulla, Rebeca Lapresa, Marina Garcia-Macia, Veronica Bobo-Jimenez, et al.. Weak neuronal glycolysis sustains cognition and organismal fitness. Nature Metabolism, 2023, ⟨10.1038/s42255-024-01049-0⟩. ⟨hal-04224688⟩
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