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Preprints, Working Papers, ... (Preprint) Year : 2023

Weak neuronal glycolysis sustains cognition and organismal fitness

Daniel Jimenez-Blasco
  • Function : Author
Jesús Agulla
  • Function : Author
Rebeca Lapresa
  • Function : Author
Marina Garcia-Macia
  • Function : Author
Veronica Bobo-Jimenez
  • Function : Author
Dario Garcia-Rodriguez
  • Function : Author
Israel Manjarrez-Raza
  • Function : Author
Emilio Fernandez
  • Function : Author
Yannick Jeanson
  • Function : Author
Spiro Khoury
  • Function : Author
Daniel Padro
  • Function : Author
Pedro Ramos-Cabrer
Peter Carmeliet
  • Function : Author
Angeles Almeida
  • Function : Author
Juan P Bolaños
  • Function : Author
  • PersonId : 1085350

Abstract

apparent paradox, neurons only weakly metabolize glucose through glycolysis, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (Pfkfb3), a key glycolysis-promoting enzyme. To evaluate the in vivo physiological significance of this hypo-glycolytic 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 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 corrected these alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions.
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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. 2023. ⟨hal-04224688⟩
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