Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington's disease

N. Brustovetsky, R. LaFrance, K. J. Purl, T. Brustovetsky, C. D. Keene, W. C. Low, Janet M. Dubinsky

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Abstract

Striatal and cortical mitochondria from knock-in and transgenic mutant huntingtin mice were examined for their sensitivity to calcium induction of the permeability transition, a cause of mitochondrial depolarization and ATP loss. The permeability transition has been suggested to contribute to cell death in Huntington's Disease. Mitochondria were examined from slowly progressing knock-in mouse models with different length polyglutarnine expansions (Q20, Q50, Q92, Q111) and from the rapidly progressing transgenic R6/2 mice overexpressing exon I of human huntingtin with more than 110 polyglutamines. As previously observed in rats, striatal mitochondria from background strain CD1 and C57BU6 control mice were more sensitive to calcium than cortical mitochondria. Between 5 and 12 months in knock-in Q92 mice and between 8 and 12 weeks in knock-in Q111 mice, striatal mitochondria developed resistance, becoming equally sensitive to calcium as cortical mitochondria, while those from Q50 mice were unchanged. Cortical mitochondrial calcium sensitivity did not change. In R6/2 mice striatal and cortical mitochondria were equally resistant to Ca2+ while striatal mitochondria from littermate controls were more susceptible. No increases in calcium sensitivity were observed in the mitochondria from Huntington's Disease (HD) mice compared to controls. Neither motor abnormalities, nor expression of cyclophilin D corresponded to the changes in mitochondrial sensitivity. Polyglutamine expansions in huntingtin produced an early increased resistance to calcium in striatal mitochondria suggesting mitochondria undergo compensatory changes in calcium sensitivity in response to the many cellular changes wrought by polyglutamine expansion.

Original languageEnglish (US)
Pages (from-to)1361-1370
Number of pages10
JournalJournal of Neurochemistry
Volume93
Issue number6
DOIs
StatePublished - Jun 1 2005

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Keywords

  • CAG repeat diseases
  • Differential susceptibility
  • Excitotoxicity
  • Permeability transition
  • Regional brain mitochondria

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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