ArticleThe Journal of biological chemistry2011
Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 80 citations in OpenAlex.
- Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2022Trial
- Low lysine diet in glutaric aciduria type I--effect on anthropometric and biochemical follow-up parameters.Journal of inherited metabolic disease · 2013Trial
- Glutaric aciduria type 1 presenting with Parkinsonism with presynaptic dopaminergic dysfunction in an adult female: a case report.Neurogenetics · 2026Article
- Aminoadipate-semialdehyde synthase, a potential target for substrate reduction therapy in glutaric aciduria type 1.Scientific reports · 2026Article
- Untargeted LC-HRMS of Dried Blood Spots Reveals Metabolic Alterations and Candidate Biomarkers in Glutaric Aciduria Type-1.Metabolites · 2026Article
- Cerebral White Matter Alterations Associated With Oligodendrocyte Vulnerability in Organic Acidurias: Insights in Glutaric Aciduria Type I.Neurotoxicity research · 2024Review
- Dual Effect of Carnosine on ROS Formation in Rat Cultured Cortical Astrocytes.Molecular neurobiology · 2024Article
- Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma.Science advances · 2022Article
- The biochemical subtype is a predictor for cognitive function in glutaric aciduria type 1: a national prospective follow-up study.Scientific reports · 2021Observational
- Characterization of novelMolecular genetics and metabolism reports · 2019Article
- Neurological manifestations of organic acidurias.Nature reviews. Neurology · 2019Review
- Long Lasting High Lysine Diet Aggravates White Matter Injury in Glutaryl-CoA Dehydrogenase Deficient (Gcdh-/-) Mice.Molecular neurobiology · 2019Article
- Organic acidurias in adults: late complications and management.Journal of inherited metabolic disease · 2018Review
- The effect of succinate on brain NADH/NADScientific reports · 2018Article
- Impairment of astrocytic glutaminolysis in glutaric aciduria type I.Journal of inherited metabolic disease · 2018Article
- Glutaric Aciduria Type 1 and Acute Renal Failure: Case Report and Suggested Pathomechanisms.JIMD reports · 2018Article
- Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I.Molecular neurobiology · 2017Article
- Focally perfused succinate potentiates brain metabolism in head injury patients.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2017Article
- Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay.Molecular medicine (Cambridge, Mass.) · 2016Article
- A cross-sectional controlled developmental study of neuropsychological functions in patients with glutaric aciduria type I.Orphanet journal of rare diseases · 2015Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
The inherited neurodegenerative disorder glutaric aciduria type 1 (GA1) results from mutations in the gene for the mitochondrial matrix enzyme glutaryl-CoA dehydrogenase (GCDH), which leads to elevations of the dicarboxylates glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in brain and blood. The characteristic clinical presentation of GA1 is a sudden onset of dystonia during catabolic situations, resulting from acute striatal injury. The underlying mechanisms are poorly understood, but the high levels of GA and 3OHGA that accumulate during catabolic illnesses are believed to play a primary role. Both GA and 3OHGA are known to be substrates for Na(+)-coupled dicarboxylate transporters, which are required for the anaplerotic transfer of the tricarboxylic acid cycle (TCA) intermediate succinate between astrocytes and neurons. We hypothesized that GA and 3OHGA inhibit the transfer of succinate from astrocytes to neurons, leading to reduced TCA cycle activity and cellular injury. Here, we show that both GA and 3OHGA inhibit the uptake of [(14)C]succinate by Na(+)-coupled dicarboxylate transporters in cultured astrocytic and neuronal cells of wild-type and Gcdh(-/-) mice. In addition, we demonstrate that the efflux of [(14)C]succinate from Gcdh(-/-) astrocytic cells mediated by a not yet identified transporter is strongly reduced. This is the first experimental evidence that GA and 3OHGA interfere with two essential anaplerotic transport processes: astrocytic efflux and neuronal uptake of TCA cycle intermediates, which occur between neurons and astrocytes. These results suggest that elevated levels of GA and 3OHGA may lead to neuronal injury and cell death via disruption of TCA cycle activity.
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