Abstract |
Mitochondrial dysfunction has been proposed to play an important role in the neuropathology of glutaric acidemia type I (GA I). However, the relevance of bioenergetics disruption and the exact mechanisms responsible for the cortical leukodystrophy and the striatum degeneration presented by GA I patients are not yet fully understood. Therefore, in the present work we measured the respiratory chain complexes activities I-IV, mitochondrial respiratory parameters state 3, state 4, the respiratory control ratio and dinitrophenol (DNP)-stimulated respiration (uncoupled state), as well as the activities of α-ketoglutarate dehydrogenase (α-KGDH), creatine kinase (CK) and Na+, K+- ATPase in cerebral cortex, striatum and hippocampus from 30-day-old Gcdh-/- and wild type (WT) mice fed with a normal or a high Lys (4.7%) diet. When a baseline (0.9% Lys) diet was given, we verified mild alterations of the activities of some respiratory chain complexes in cerebral cortex and hippocampus, but not in striatum from Gcdh-/- mice as compared to WT animals. Furthermore, the mitochondrial respiratory parameters and the activities of α-KGDH and CK were not modified in all brain structures from Gcdh-/- mice. In contrast, we found a significant reduction of Na(+), K(+)- ATPase activity associated with a lower degree of its expression in cerebral cortex from Gcdh-/- mice. Furthermore, a high Lys (4.7%) diet did not accentuate the biochemical alterations observed in Gcdh-/- mice fed with a normal diet. Since Na(+), K(+)- ATPase activity is required for cell volume regulation and to maintain the membrane potential necessary for a normal neurotransmission, it is presumed that reduction of this enzyme activity may represent a potential underlying mechanism involved in the brain swelling and cortical abnormalities (cortical atrophy with leukodystrophy) observed in patients affected by GA I.
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Authors | Alexandre Umpierrez Amaral, Bianca Seminotti, Cristiane Cecatto, Carolina Gonçalves Fernandes, Estela Natacha Brandt Busanello, Ângela Zanatta, Luiza Wilges Kist, Maurício Reis Bogo, Diogo Onofre Gomes de Souza, Michael Woontner, Stephen Goodman, David M Koeller, Moacir Wajner |
Journal | Molecular genetics and metabolism
(Mol Genet Metab)
Vol. 107
Issue 3
Pg. 375-82
(Nov 2012)
ISSN: 1096-7206 [Electronic] United States |
PMID | 22999741
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 Elsevier Inc. All rights reserved. |
Chemical References |
- Ketoglutarate Dehydrogenase Complex
- Glutaryl-CoA Dehydrogenase
- Creatine Kinase
- Sodium-Potassium-Exchanging ATPase
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Topics |
- Amino Acid Metabolism, Inborn Errors
(enzymology, genetics, pathology)
- Animals
- Brain Diseases, Metabolic
(enzymology, genetics, pathology)
- Cerebral Cortex
(enzymology, pathology)
- Corpus Striatum
(enzymology, pathology)
- Creatine Kinase
(genetics, metabolism)
- Down-Regulation
- Electron Transport
(genetics)
- Food, Formulated
- Gene Expression
- Glutaryl-CoA Dehydrogenase
(deficiency, genetics)
- Hippocampus
(enzymology, pathology)
- Humans
- Ketoglutarate Dehydrogenase Complex
(genetics, metabolism)
- Mice
- Mice, Knockout
- Mitochondria
(genetics, metabolism)
- Oxidative Phosphorylation
- Sodium-Potassium-Exchanging ATPase
(genetics, metabolism)
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