title: Dysfunctional mitochondrial respiration in the striatum of the Huntington's disease transgenic R6/2 mouse model.
abstract: Metabolic dysfunction and mitochondrial involvement are recognised as part of the pathology in Huntington's Disease (HD). Post-mortem examinations of the striatum from end-stage HD patients have shown a decrease in the in vitro activity of complexes II, III and IV of the electron transport system (ETS). In different models of HD, evidence of enzyme defects have been reported in complex II and complex IV using enzyme assays. However, such assays are highly variable and results have been inconsistent. We investigated the integrated ETS function ex vivo using a sensitive high-resolution respirometric (HRR) method. The O2 flux in a whole-cell sample combined with the addition of mitochondrial substrates, uncouplers and inhibitors enabled us to accurately quantitate the function of individual mitochondrial complexes in intact mitochondria, while retaining mitochondrial regulation and compensatory mechanisms. We used HRR to examine the mitochondrial function in striata from 12-week old R6/2 mice expressing exon 1 of human HTT with 130 CAG repeats. A significant reduction in complex II and complex IV flux control ratios was found in the R6/2 mouse striatum at 12 weeks of age compared to controls, confirming previous findings obtained with spectrophotometric enzyme assays.
authors.affiliation: Institute of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen; Section of Molecular Medicine, Department of Clinical Biochemistry, Genetics and Immunology, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Frederik Heurlin
authors.initials: FH
authors.lastname: Aidt
authors.forename: Signe Marie Borch
authors.initials: SM
authors.lastname: Nielsen
authors.forename: Jørgen
authors.initials: J
authors.lastname: Kanters
authors.forename: Dominik
authors.initials: D
authors.lastname: Pesta
authors.forename: Troels Tolstrup
authors.initials: TT
authors.lastname: Nielsen
authors.forename: Anne
authors.initials: A
authors.lastname: Nørremølle
authors.forename: Lis
authors.initials: L
authors.lastname: Hasholt
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Christian Munch
authors.initials: CM
authors.lastname: Hagen