TY - JOUR
T1 - Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice
T2 - A possible mechanism for brain injury in glutaric aciduria type I
AU - Amaral, Alexandre Umpierrez
AU - Seminotti, Bianca
AU - Cecatto, Cristiane
AU - Fernandes, Carolina Gonçalves
AU - Busanello, Estela Natacha Brandt
AU - Zanatta, Ângela
AU - Kist, Luiza Wilges
AU - Bogo, Maurício Reis
AU - de Souza, Diogo Onofre Gomes
AU - Woontner, Michael
AU - Goodman, Stephen
AU - Koeller, David M.
AU - Wajner, Moacir
N1 - Funding Information:
We are grateful to the financial support of CNPq , PROPESq/UFRGS , FAPERGS , PRONEX , FINEP Rede Instituto Brasileiro de Neurociência (IBN-Net) # 01.06.0842-00 , Instituto Nacional de Ciência e Tecnologia-Excitotoxicidade e Neuroproteção (INCT-EN) and Instituto Nacional de Ciência e Tecnologia-Translacional em Medicina (INCT-TM).
PY - 2012/11
Y1 - 2012/11
N2 - 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.
AB - 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.
KW - Brain bioenergetics
KW - Gcdh-/- mice
KW - Glutaric acidemia type I
KW - Na, K-ATPase activity and expression
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UR - http://www.scopus.com/inward/citedby.url?scp=84867898648&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2012.08.016
DO - 10.1016/j.ymgme.2012.08.016
M3 - Article
C2 - 22999741
AN - SCOPUS:84867898648
SN - 1096-7192
VL - 107
SP - 375
EP - 382
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 3
ER -