Weak neuronal glycolysis sustains cognition and organismal fitness

• Published in: Nature metabolism Vol. 6; no. 7; pp. 1253 - 1267
• Main Authors: Jimenez-Blasco, Daniel, Agulla, Jesús, Lapresa, Rebeca, Garcia-Macia, Marina, Bobo-Jimenez, Veronica, Garcia-Rodriguez, Dario, Manjarres-Raza, Israel, Fernandez, Emilio, Jeanson, Yannick, Khoury, Spiro, Portais, Jean-Charles, Padro, Daniel, Ramos-Cabrer, Pedro, Carmeliet, Peter, Almeida, Angeles, Bolaños, Juan P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2024; Nature Publishing Group
• Subjects: 13/31; 38/44; 38/47; 631/378/340; 631/45/882; 64/60; 96/95; Animals; Biomedical and Life Sciences; Cognition - physiology; Energy Metabolism; Glucose - metabolism; Glycolysis; Letter; Life Sciences; Mice; Mitochondria - metabolism; NAD - metabolism; Neurons - metabolism; Phosphofructokinase-2 - genetics; Phosphofructokinase-2 - metabolism; neuronal glycolysis
• ISSN: 2522-5812; 2522-5812
• DOI: 10.1038/s42255-024-01049-0

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.
Jiménez-Blasco et al. show that neurons exhibit moderately low glycolytic rates despite their activity being mainly supported by glucose to preserve redox balance.