Mitochondrial dysfunction in Huntington's disease: the bioenergetics of isolated and in situ mitochondria from transgenic mice.
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 Hdh150 knock-in) and wild-type littermates with the first determination of in situ respiratory parameters in intact HD striatal neurons. We assess the Ca2+-loading capacity of isolated mitochondria by steady Ca2+-infusion. Mitochondria from R6/2 mice (12-13 weeks) and 12 months YAC128, but not homozygous or heterozygous Hdh150 knock-in mice (15-17 weeks), exhibit increased Ca2+-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 Hdh150 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 Ca2+-handling), Hdh150 neurons are more vulnerable to Ca2+-deregulation than neurons from their wild-type littermates. These results stress the importance of assessing HD mitochondrial function in the cellular context.
Oliveira
Jorge M A
JM
Buck Institute for Age Research, Novato, California, USA.
Jekabsons
Mika B
MB
Chen
Sylvia
S
Lin
Amy
A
Rego
A Cristina
AC
Gonçalves
Jorge
J
Ellerby
Lisa M
LM
Nicholls
David G
DG
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D020013:Calcium Signaling / Q000235:genetics; D019069:Cell Respiration / Q000235:genetics; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate