Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells

Jessica Lamp, Britta Keyser, David Koeller, Kurt Ullrich, Thomas Braulke, Chris Mühlhausen

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 [ 14C]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 [14C]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.

Original languageEnglish (US)
Pages (from-to)17777-17784
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number20
DOIs
StatePublished - May 20 2011

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Succinic Acid
Metabolites
Citric Acid Cycle
Dicarboxylic Acid Transporters
Astrocytes
Neurons
Activity Cycles
Glutaryl-CoA Dehydrogenase
Wounds and Injuries
Corpus Striatum
Mitochondrial Genes
Dystonia
Cell death
glutaric acid
Glutaric Acidemia I
Neurodegenerative Diseases
Brain
Blood
Cell Death
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. / Lamp, Jessica; Keyser, Britta; Koeller, David; Ullrich, Kurt; Braulke, Thomas; Mühlhausen, Chris.

In: Journal of Biological Chemistry, Vol. 286, No. 20, 20.05.2011, p. 17777-17784.

Research output: Contribution to journalArticle

Lamp, Jessica ; Keyser, Britta ; Koeller, David ; Ullrich, Kurt ; Braulke, Thomas ; Mühlhausen, Chris. / Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 20. pp. 17777-17784.
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