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Mitochondrial dysfunction in Huntington’s disease: the bioenergetics of isolated and in situ mitochondria from transgenic mice
Author(s) -
Oliveira Jorge M. A.,
Jekabsons Mika B.,
Chen Sylvia,
Lin Amy,
Rego A. Cristina,
Gonçalves Jorge,
Ellerby Lisa M.,
Nicholls David G.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04361.x
Subject(s) - huntingtin , mitochondrion , huntington's disease , bioenergetics , biology , genetically modified mouse , transgene , forebrain , microbiology and biotechnology , wild type , context (archaeology) , medicine , endocrinology , mutant , biochemistry , central nervous system , gene , disease , paleontology
Mitochondrial dysfunction is believed to participate in Huntington’s disease (HD) pathogenesis. Here we compare the bioenergetic behavior of forebrain mitochondria isolated from different transgenic HD mice (R6/2, YAC128 and Hdh 150 knock‐in) and wild‐type littermates with the first determination of in situ respiratory parameters in intact HD striatal neurons. We assess the Ca 2+ ‐loading capacity of isolated mitochondria by steady Ca 2+ ‐infusion. Mitochondria from R6/2 mice (12–13 weeks) and 12 months YAC128, but not homozygous or heterozygous Hdh 150 knock‐in mice (15–17 weeks), exhibit increased Ca 2+ ‐loading capacity when compared with respective wild‐type littermates. In situ mitochondria in intact striatal neurons show high respiratory control. Moreover, moderate expression of full‐length mutant huntingtin (in Hdh 150 knock‐in heterozygotes) does not significantly impair mitochondrial respiration in unstimulated neurons. However, when challenged with energy‐demanding stimuli (NMDA‐receptor activation in pyruvate‐based media to accentuate the mitochondria role in Ca 2+ ‐handling), Hdh 150 neurons are more vulnerable to Ca 2+ ‐deregulation than neurons from their wild‐type littermates. These results stress the importance of assessing HD mitochondrial function in the cellular context.