Biology subjects

Agulla, J.

Publications and source records attributed to Agulla, J..

5 recordsLinked to original sources

bioRxiv2026

Mitochondrial pyruvate import in astrocytes links anaplerosis to seizure resistance

Astrocytes are glycolytic cells that convert a substantial fraction of glucose-derived pyruvate into lactate, a metabolite implicated in supporting neuronal energy demand and modulating excitability, plasticity and memory. This view has placed astrocytic lactate production and export at the centre of astrocyte-neuron metabolic coupling, but whether mitochondrial pyruvate utilization in astrocytes is dispensable in vivo or fulfils an essential function in the intact brain remains unknown. Here we show that adult astrocyte-specific deletion of Mpc2, encoding an obligatory mitochondrial pyruvate carrier subunit, causes motor deficits, neuronal hyperexcitability and seizure-associated lethality. Metabolic profiling revealed pyruvate diversion toward alanine as an unsuccessful compensatory bypass, together with impaired tricarboxylic acid-cycle metabolism and an imbalance in neurotransmitter-related pools, including glutamate, glutamine and {gamma}-aminobutyric acid. Thus, astrocytic mitochondrial pyruvate import is not primarily required for bioenergetic purposes but acts as a non-redundant anaplerotic gate that maintains neurotransmitter homeostasis, excitation-inhibition balance and seizure resistance in vivo.

neuroscience↗

bioRxiv2025

Astrocytic glycolysis attenuates mitochondrial efficiency to preserve cognition

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.

cell biology↗

bioRxiv2023

Weak neuronal glycolysis sustains cognition and organismal fitness

The energy cost of neuronal activity is mainly sustained by glucose1,2. However, in an apparent paradox, neurons only weakly metabolize glucose through glycolysis3,4,5,6, 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 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.

cell biology↗

bioRxiv2022

Mitochondrial sodium/calcium exchanger NCLX regulates glycolysis in astrocytes, impacting on cognitive performance

Intracellular Ca2+ concentrations are strictly controlled by plasma membrane transporters, the endoplasmic reticulum, and mitochondria, in which Ca2+ uptake is mediated by the mitochondrial calcium uniporter complex (MCUc), while efflux occurs mainly through the mitochondrial Na+/Ca2+ exchanger (NCLX). RNAseq database repository searches led us to identify the Nclx transcript as highly enriched in astrocytes when compared to neurons. To assess the role of NCLX in mouse primary culture astrocytes, we inhibited its function both pharmacologically or genetically. This resulted in re-shaping of cytosolic Ca2+ signaling and a metabolic shift that increased glycolytic flux and lactate secretion in a Ca2+-dependent manner. Interestingly, in vivo genetic deletion of NCLX in hippocampal astrocytes improved cognitive performance in behavioral tasks, whereas hippocampal neuron-specific deletion of NCLX impaired cognitive performance. These results unveil a role for NCLX as a novel modulator of astrocytic glucose metabolism, impacting on cognition.

biochemistry↗

bioRxiv2018

Amyloid-β promotes neurotoxicity by Cdk5-induced p53 stabilization

The p53 tumor suppressor protein, a key regulator of cell apoptosis, has been described to accumulate in affected brain areas from Alzheimers disease (AD) patients. However, whether p53 plays any role in AD pathogenesis remains unknown. Here, we found that exposure of neurons to oligomers of the amyloidogenic fragment 25-35 of the A{beta} peptide (A{beta}25-35) activated Cdk5, which promoted p53 protein phosphorylation and stabilization. Moreover, A{beta}25-35-mediated mitochondrial dysfunction and neuronal apoptosis were prevented by both genetic and pharmacological inhibition of either p53 or Cdk5 activities. To confirm this mechanism in vivo, A{beta}25-35 was stereotaxically injected in the cerebral right ventricle of mice, a treatment that caused p53 protein accumulation, dendrite disruption and neuronal death. Furthermore, these effects were prevented in p53 knockout mice or by pharmacologically inhibiting p53. Thus, A{beta}25-35 triggers Cdk5 activation to induce p53 phosphorylation and stabilization, which leads to neuronal damage. Inhibition of the Cdk5-p53 pathway may therefore represent a novel therapeutic strategy against A{beta}-induced neurodegeneration.

neuroscience↗