ArticleSchizophrenia research2014
Abnormal partitioning of hexokinase 1 suggests disruption of a glutamate transport protein complex in schizophrenia.
Article in Schizophrenia research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 51 citations in OpenAlex.
- De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment.European journal of human genetics : EJHG · 2019Trial
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Gestational Hypoxia Disrupts Medial Ganglionic Eminence Progenitor Dynamics and Interneuron Development in Schizophrenia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Aberrant Modular Dynamics of Functional Networks in Schizophrenia and Their Relationship With Neurotransmitter and Gene Expression Profiles.Human brain mapping · 2025Article
- Dysregulated Transcript Expression but Not Function of the Glutamate Transporter EAAT2 in the Dorsolateral Prefrontal Cortex in Schizophrenia.Schizophrenia bulletin · 2025Article
- Mitochondrial dysfunction in psychiatric disorders.Schizophrenia research · 2024Review
- Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency.Nature metabolism · 2024Article
- Metabolic Insights into Neuropsychiatric Illnesses and Ketogenic Therapies: A Transcriptomic View.International journal of molecular sciences · 2024Article
- Sleep, mood disorders, and the ketogenic diet: potential therapeutic targets for bipolar disorder and schizophrenia.Frontiers in psychiatry · 2024Review
- Exploring the role of ketone bodies in the diagnosis and treatment of psychiatric disorders.Frontiers in psychiatry · 2023Review
- Altered purinergic receptor expression in the frontal cortex in schizophrenia.Schizophrenia (Heidelberg, Germany) · 2022Article
- Schizophrenia: a disorder of broken brain bioenergetics.Molecular psychiatry · 2022Review
- Astrocyte Bioenergetics and Major Psychiatric Disorders.Advances in neurobiology · 2021Review
- Prefrontal cortical alterations of glutamate and GABA neurotransmission in schizophrenia: Insights for rational biomarker development.Biomarkers in neuropsychiatry · 2020Article
- Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia.Molecular psychiatry · 2019Article
- Abnormal ER quality control of neural GPI-anchored proteins via dysfunction in ER export processing in the frontal cortex of elderly subjects with schizophrenia.Translational psychiatry · 2019Article
- Spatial control of neuronal metabolism through glucose-mediated mitochondrial transport regulation.eLife · 2018Article
- Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders.World journal of psychiatry · 2018Review
- Regulation of mitochondrial dynamics in astrocytes: Mechanisms, consequences, and unknowns.Glia · 2018Review
- Defects in Bioenergetic Coupling in Schizophrenia.Biological psychiatry · 2018Review
Corrections and comments
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Authors and funding
6 authors at 5 institutions in 1 country.
Funding
Abstract
Excitatory amino acid transporter 2 (EAAT2) belongs to a family of Na(+) dependent glutamate transporters that maintain a low synaptic concentration of glutamate by removing glutamate from the synaptic cleft into astroglia and neurons. EAAT2 activity depends on Na(+) and K(+) gradients generated by Na(+)/K(+) ATPase and ATP. Hexokinase 1 (HK1), an initial enzyme of glycolysis, binds to mitochondrial outer membrane where it couples cytosolic glycolysis to mitochondrial oxidative phosphorylation, producing ATP utilized by the EAAT2/Na(+)/K(+) ATPase protein complex to facilitate glutamate reuptake. In this study, we hypothesized that the protein complex formed by EAAT2, Na(+)/K(+) ATPase and mitochondrial proteins in human postmortem prefrontal cortex may be disrupted, leading to abnormal glutamate transmission in schizophrenia. We first determined that EAAT2, Na(+)/K(+) ATPase, HK1 and aconitase were found in both EAAT2 and Na(+)/K(+) ATPase interactomes by immunoisolation and mass spectrometry in human postmortem prefrontal cortex. Next, we measured levels of glutamate transport complex proteins in subcellular fractions in the dorsolateral prefrontal cortex and found increases in the EAAT2B isoform of EAAT2 in a fraction containing extrasynaptic membranes and increased aconitase 1 in a mitochondrial fraction. Finally, an increased ratio of HK1 protein in the extrasynaptic membrane/mitochondrial fraction was found in subjects with schizophrenia, suggesting that HK1 protein is abnormally partitioned in this illness. Our findings indicate that the integrity of the glutamate transport protein complex may be disrupted, leading to decreased perisynaptic buffering and reuptake of glutamate, as well as impaired energy metabolism in schizophrenia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.