GATOR1 signaling defects promote astrocytic metabolic rewiring and excitatory neurotransmitter cycling.

Overview

Authors: Imane Hadj-Aissa¹, Maéline Muller¹, Jorge Soliz², Chantelle F Sephton¹, Paul A Dutchak¹

ORCID iDs: Imane Hadj-Aissa, Maéline Muller, Chantelle F Sephton, Paul A Dutchak

Department of Psychiatry and Neuroscience, CERVO Brain Research Centre, Université Laval,Québec City, QC G1J 2G3 Canada
Centre de Recherche de l’Institute Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval,Québec City, QC G1V 4G5 Canada

Institutions: Université Laval (Canada); Institut universitaire de cardiologie et de pneumologie de Québec (Canada)

Journal: EMBO reports, volume 27, issue 15, pages 4252-4271

Dates: received 1 October 2025; accepted 10 June 2026; published online 3 July 2026; in print August 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s44319-026-00846-w · PMID 42399454 · PMCID PMC13458053 · OpenAlex W7167264287

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: human (organism), mouse (organism), cellular / molecular (subfield)

Methods: Spectral & time-frequency, Statistics

Keywords: Metabolism, Neuroscience

MeSH: Astrocytes*, Neurotransmitter Agents*, Signal Transduction*, Animals, Electron Transport Complex II, Glutamic Acid, Glutamine, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Mitochondria, Oxidation-Reduction, Reactive Oxygen Species, TOR Serine-Threonine Kinases (* major topic)

Topic: Neuroscience and Neuropharmacology Research (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex

Funding: Natural Sciences and Engineering Research Council of Canada (RGPIN-2018-06227, DGECR-2018-00093, RGPIN-2020-06376, DGECR-2020-00060); Brain Canada Foundation (Future Leaders in Canadian Brain Research program); Canadian Institutes of Health Research (202409PJT-526975, 202309PJT-506236, IC135391)

Citations: not cited yet (Europe PMC); 40 references in the paper

Abstract

GATOR1 is an evolutionarily-conserved negative regulator of mTORC1-dependent signal transduction with pathogenic mutations linked to epilepsy, infantile spasms, and autism spectrum disorders. While a biochemical role of GATOR1 in amino acid-signaling is established, its cell-type specific contributions within the brain remain poorly defined. Here, we show that loss of GATOR1 function in astrocytic cells disrupts mitochondrial metabolism, with a selective dysfunction of the electron transport chain Complex II leading to elevated reactive oxygen species (ROS) and redox imbalance. These changes are accompanied by compensatory increases in antioxidant regulatory systems including superoxide dismutase, but remain insufficient to ameliorate the increased ROS. GATOR1-deficient astrocytes show metabolic rewiring marked by enhanced expression of glutamate uptake and glutamine synthesis pathways that contribute to the glutamate-glutamine cycle governing neuronal glutamine availability and synaptic homeostasis. In vivo, GATOR1 deficiency results in progressive astrocytic reactivity, seizures, and a reduced lifespan. These findings demonstrate that GATOR1 function is critical to coordinate astrocytic mitochondrial activity and neurotransmitter cycling pathways, establishing a novel link between intracellular amino acid-signaling in astrocytes and excitatory neural network homeostasis.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Data links

ebi.ac.uk/biostudies/sourcedata, EMBL-EBI; found in the notes

Data availability

This study includes no data deposited in external repositories.

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44319-026-00846-w (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44319-026-00846-w).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 2 keywords, 14 MeSH terms, 3 funders, 40 references.

Cite

This paper

Hadj-Aissa, I., Muller, M., Soliz, J., Sephton, C. F., & Dutchak, P. A. (2026). GATOR1 signaling defects promote astrocytic metabolic rewiring and excitatory neurotransmitter cycling. EMBO reports, 27(15), 4252-4271. https://doi.org/10.1038/s44319-026-00846-w

BibTeX

@article{hadjaissa2026gator1, author = {Hadj-Aissa, Imane and Muller, Maéline and Soliz, Jorge and Sephton, Chantelle F and Dutchak, Paul A}, title = {{GATOR1 signaling defects promote astrocytic metabolic rewiring and excitatory neurotransmitter cycling}}, journal = {EMBO reports}, year = {2026}, month = jul, volume = {27}, number = {15}, pages = {4252--4271}, publisher = {Nature Publishing Group}, issn = {1469-221X}, doi = {10.1038/s44319-026-00846-w}, url = {https://doi.org/10.1038/s44319-026-00846-w}, pmid = {42399454}, pmcid = {PMC13458053} }

RIS

TY - JOUR AU - Hadj-Aissa, Imane AU - Muller, Maéline AU - Soliz, Jorge AU - Sephton, Chantelle F AU - Dutchak, Paul A TI - GATOR1 signaling defects promote astrocytic metabolic rewiring and excitatory neurotransmitter cycling T2 - EMBO reports J2 - EMBO Rep PY - 2026 DA - 2026/07/03 VL - 27 IS - 15 SP - 4252 EP - 4271 SN - 1469-221X PB - Nature Publishing Group DO - 10.1038/s44319-026-00846-w UR - https://doi.org/10.1038/s44319-026-00846-w LA - en ER -

CSL-JSON

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