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.

Oxidative metabolism and Ca 2+ handling in striatal mitochondria from YAC128 mice, a model of Huntington's disease

“…Consequently, impairment of mitochondrial respiration may affect both oxidative phosphorylation and Ca 2+ uptake. There are several reports suggesting mitochondrial respiratory deficits in various HD models (Tabrizi et al, 2000; Damiano et al, 2013; Aidt et al, 2013). However, our recent studies demonstrated the lack of defects in oxidative metabolism in mitochondria isolated from the whole HD brains and in cultured cortical and striatal neurons derived from HD mice (Hamilton et al, 2015; Hamilton et al, 2016).…”

“…Earlier findings suggested abnormalities in mitochondrial respiration and defects in Ca 2+ handling in mitochondria from HD mouse and cell models (Tabrizi et al, 2000; Damiano et al, 2013; Aidt et al, 2013; Panov et al, 2002; Choo et al, 2004; Lim et al, 2008). In our previous studies, we tested the possible deleterious effects of mHtt on mitochondrial oxidative metabolism and Ca 2+ handling using isolated nonsynaptic and synaptic mitochondria from the whole brain of HD mice (Pellman et al, 2015; Hamilton et al, 2015; Hamilton et al, 2016).…”

Mitochondrial bioenergetic alterations after focal traumatic brain injury in the immature brain

“…However, the enzyme itself may be altered following injury devoid of any alteration in mitochondrial content (Chepelev et al, 2009). In addition, flux control ratios were assessed as an internal normalization of the respiratory states to the maximal uncoupler-induced rate of respiration within the ETS, a method that may be independent of tissue heterogeneity (Aidt et al, 2013). All of these methods have strengths and weaknesses, thus we decided to present data for each respiratory state in response to injury multiple ways: tissue mass, FCR, CS activity, as well as ratios for evaluating coupling of respiration to ATP production and the relative contribution of complex I- and II-driven respiration to maximal flux.…”

Amitriptyline Improves Motor Function via Enhanced Neurotrophin Signaling and Mitochondrial Functions in the Murine N171-82Q Huntington Disease Model

“…Cytochrome c oxidase (complex IV) is an intracellular measure of oxidative energy metabolic capacity and respiration (72). Complex IV activity is decreased in the mitochondria from both HD patients (14) and HD mice (73). Both VDAC and complex IV are regarded as classic mitochondrial markers, suggesting that AMI treatment has provided considerable mitochondrial support in these mice.…”