Portal de investigación
Weak neuronal glycolysis sustains cognition and organismal fitness
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Autores de IBSAL
Autores ajenos a IBSAL
- Jeanson, Y
- Khoury, S
- Portais, JC
- Padro, D
- Ramos-Cabrer, P
- Carmeliet, P
Grupos
Abstract
The energy cost of neuronal activity is mainly sustained by glucose 1,2 . However, in an apparent paradox, neurons modestly metabolize glucose through glycolysis 3-6 , 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. Jim & eacute;nez-Blasco et al. show that neurons exhibit moderately low glycolytic rates despite their activity being mainly supported by glucose to preserve redox balance.
Datos de la publicación
- ISSN/ISSNe:
- 2522-5812, 2522-5812
- Tipo:
- Article
- Páginas:
- -
- PubMed:
- 38789798
Nature Metabolism NATURE PUBLISHING GROUP
Citas Recibidas en Web of Science: 15
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- No hay documentos
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Cita
Jimenez D,Agulla J,Lapresa R,Garcia M,Bobo V,Garcia D,Manjarres I,Fernandez E,Jeanson Y,Khoury S,Portais JC,Padro D,Ramos P,Carmeliet P,Almeida A,Bolanos JP. Weak neuronal glycolysis sustains cognition and organismal fitness. Nat Metab. 2024. 6. (7):IF:18,900. (1).