title: Oxidative metabolism in YAC128 mouse model of Huntington's disease.
abstract: Alterations in oxidative metabolism are considered to be one of the major contributors to Huntington's disease (HD) pathogenesis. However, existing data about oxidative metabolism in HD are contradictory. Here, we investigated the effect of mutant huntingtin (mHtt) on oxidative metabolism in YAC128 mice. Both mHtt and wild-type huntingtin (Htt) were associated with mitochondria and the amount of bound Htt was four-times higher than the amount of bound mHtt. Percoll gradient-purified brain synaptic and non-synaptic mitochondria as well as unpurified brain, liver and heart mitochondria, isolated from 2- and 10-month-old YAC128 mice and age-matched WT littermates had similar respiratory rates. There was no difference in mitochondrial membrane potential or ADP and ATP levels. Expression of selected nuclear-encoded mitochondrial proteins in 2- and 10-month-old YAC128 and WT mice was similar. Cultured striatal and cortical neurons from YAC128 and WT mice had similar respiratory and glycolytic activities as measured with Seahorse XF24 analyzer in medium containing 10 mm glucose and 15 mm pyruvate. In the medium with 2.5 mm glucose, YAC128 striatal neurons had similar respiration, but slightly lower glycolytic activity. Striatal neurons had lower maximal respiration compared with cortical neurons. In vivo experiments with YAC128 and WT mice showed similar O2 consumption, CO2 release, physical activity, food consumption and fasted blood glucose. However, YAC128 mice were heavier and had more body fat compared with WT mice. Overall, our data argue against respiratory deficiency in YAC128 mice and, consequently, suggest that mitochondrial respiratory dysfunction is not essential for HD pathogenesis.
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: James
authors.initials: J
authors.lastname: Hamilton
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Pellman
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Brustovetsky
authors.affiliation: Department of Biochemistry and Molecular Biology and Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Pharmacology and Toxicology, Department of Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA and nbrous@iu.edu.
authors.forename: Nickolay
authors.initials: N
authors.lastname: Brustovetsky
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism; D015870:Gene Expression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010641:Phenotype; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D001786:Blood Glucose; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate