Year: 2025
Type: preprint
Abstract: Astrocytic glycolysis is tightly coupled to neurotransmission and thought to be essential for neurological health. However, the metabolic adaptations that enable astrocytes to maintain a durable glycolytic profile without compromising viability are elusive. Here, using in vivo approaches including cell-specific gene expression disruption, metabolic flux analyses and behavioral tests in mice, we addressed this issue. We found that Pfkfb3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3) is instrumental in maintaining the astrocytic glycolytic phenotype. Importantly, astrocytic glycolysis sustained by Pfkfb3 is required for normal cognitive performance. Mechanistically, ATP generated through glycolysis is consumed by mitochondria, via the reverse mode of ATP synthase, to conserve the proton gradient across the inner mitochondrial membrane. This enables mitochondria to attenuate pyruvate decarboxylation, tricarboxylic acid cycle and electron transport chain activity, thereby preserving pyruvate for conversion into lactate and delivery to neurons. These findings reveal that astrocytes sacrifice mitochondrial bioenergetic efficiency as a previously underappreciated strategy to support cognition.
Authors: Paula Alonso-Batan, Daniel Jimenez-Blasco, Jesus Agulla, Rebeca Lapresa, Marta Antequera-Düwel, Sara Yunta-Sanchez, Brenda Morant-Ferrando, Dario Garcia-Rodriguez, Rebeca Acin-Perez, Veronica Bobo-Jimenez, Leticia Sancha-Ortega, Regina Mengual, Silvia Gomila, Sonia Gonzalez-Guerrero, Emilio Fernandez, Gilles Bonvento, Jose A. Enriquez, Peter Carmeliet, Angeles Almeida, Juan P. Bolaños
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: G1047435273, G2262748287, G3480869486, G3681454997, G4042783231, G425668148, Medicina Personalizada (MedPer) en la detección precoz del deterioro cognitivo (DC) preclinico. Desarrollo de un modelo predictivo de riesgo., Astrocytic metabolism-driven epigenetics at the cornerstone of cognitive aging, G6218905885, Descifrando la reprogramación metabólica en la reparación cerebral y su impacto en el pronóstico de ictus
OpenAlex ID: W7117321303