Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells.
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Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. / Lamp, Jessica; Keyser, Britta; Koeller, David M; Ullrich, Kurt; Braulke, Thomas; Mühlhausen, Chris.
in: J BIOL CHEM, Jahrgang 286, Nr. 20, 20, 2011, S. 17777-17784.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells.
AU - Lamp, Jessica
AU - Keyser, Britta
AU - Koeller, David M
AU - Ullrich, Kurt
AU - Braulke, Thomas
AU - Mühlhausen, Chris
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Mice, Knockout
KW - Neurons/metabolism
KW - Amino Acid Metabolism, Inborn Errors/genetics/metabolism
KW - Astrocytes/metabolism
KW - Biological Transport/genetics
KW - Brain/metabolism
KW - Brain Diseases, Metabolic/genetics/metabolism
KW - Cell Death/genetics
KW - Cell Line, Transformed
KW - Citric Acid Cycle/genetics
KW - Glutarates/metabolism
KW - Glutaryl-CoA Dehydrogenase/deficiency/genetics/metabolism
KW - Organic Anion Transporters/genetics/metabolism
KW - Succinic Acid/metabolism
KW - Animals
KW - Mice
KW - Mice, Knockout
KW - Neurons/metabolism
KW - Amino Acid Metabolism, Inborn Errors/genetics/metabolism
KW - Astrocytes/metabolism
KW - Biological Transport/genetics
KW - Brain/metabolism
KW - Brain Diseases, Metabolic/genetics/metabolism
KW - Cell Death/genetics
KW - Cell Line, Transformed
KW - Citric Acid Cycle/genetics
KW - Glutarates/metabolism
KW - Glutaryl-CoA Dehydrogenase/deficiency/genetics/metabolism
KW - Organic Anion Transporters/genetics/metabolism
KW - Succinic Acid/metabolism
M3 - SCORING: Journal article
VL - 286
SP - 17777
EP - 17784
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 20
M1 - 20
ER -
