Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice: A possible mechanism for brain injury in glutaric aciduria type I

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 Koeller, Moacir Wajner

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)375-382
Number of pages8
JournalMolecular Genetics and Metabolism
Volume107
Issue number3
DOIs
StatePublished - Nov 2012

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Glutaryl-CoA Dehydrogenase
Nutrition
Cerebral Cortex
Brain Injuries
Adenosine Triphosphatases
Brain
Diet
Creatine Kinase
Electron Transport
Hippocampus
Dinitrophenols
Enzyme activity
Wild Animals
Brain Edema
Swelling
Oxidoreductases
Animals
Cell Size
Synaptic Transmission
Membrane Potentials

Keywords

  • Brain bioenergetics
  • Gcdh-/- mice
  • Glutaric acidemia type I
  • Na, K-ATPase activity and expression

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice : A possible mechanism for brain injury in glutaric aciduria type I. / Amaral, Alexandre Umpierrez; Seminotti, Bianca; Cecatto, Cristiane; Fernandes, Carolina Gonçalves; Busanello, Estela Natacha Brandt; Zanatta, Ângela; Kist, Luiza Wilges; Bogo, Maurício Reis; de Souza, Diogo Onofre Gomes; Woontner, Michael; Goodman, Stephen; Koeller, David; Wajner, Moacir.

In: Molecular Genetics and Metabolism, Vol. 107, No. 3, 11.2012, p. 375-382.

Research output: Contribution to journalArticle

Amaral, AU, Seminotti, B, Cecatto, C, Fernandes, CG, Busanello, ENB, Zanatta, Â, Kist, LW, Bogo, MR, de Souza, DOG, Woontner, M, Goodman, S, Koeller, D & Wajner, M 2012, 'Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice: A possible mechanism for brain injury in glutaric aciduria type I', Molecular Genetics and Metabolism, vol. 107, no. 3, pp. 375-382. https://doi.org/10.1016/j.ymgme.2012.08.016
Amaral, Alexandre Umpierrez ; Seminotti, Bianca ; Cecatto, Cristiane ; Fernandes, Carolina Gonçalves ; Busanello, Estela Natacha Brandt ; Zanatta, Ângela ; Kist, Luiza Wilges ; Bogo, Maurício Reis ; de Souza, Diogo Onofre Gomes ; Woontner, Michael ; Goodman, Stephen ; Koeller, David ; Wajner, Moacir. / Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice : A possible mechanism for brain injury in glutaric aciduria type I. In: Molecular Genetics and Metabolism. 2012 ; Vol. 107, No. 3. pp. 375-382.
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AU - Kist, Luiza Wilges

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