title: Oxygen consumption deficit in Huntington disease mouse brain under metabolic stress.
abstract: In vivo evidence for brain mitochondrial dysfunction in animal models of Huntington disease (HD) is scarce. We applied the novel17O magnetic resonance spectroscopy (MRS) technique on R6/2 mice to directly determine rates of oxygen consumption (CMRO2) and assess mitochondrial function in vivo Basal respiration and maximal CMRO2in the presence of the mitochondrial uncoupler dinitrophenol (DNP) were compared using 16.4 T in isoflurane anesthetized wild type (WT) and HD mice at 9 weeks. At rest, striatal CMRO2of R6/2 mice was equivalent to that of WT, indicating comparable mitochondrial output despite onset of motor symptoms in R6/2. After DNP injection, the maximal CMRO2in both striatum and cortex of R6/2 mice was significantly lower than that of WT, indicating less spare energy generating capacity. In a separate set of mice, oligomycin injection to block ATP generation decreased CMRO2equally in brains of R6/2 and WT mice, suggesting oxidative phosphorylation capacity and respiratory coupling were equivalent at rest. Expression levels of representative mitochondrial proteins were compared from harvested tissue samples. Significant differences between R6/2 and WT included: in striatum, lower VDAC and the mitochondrially encoded cytochrome oxidase subunit I relative to actin; in cortex, lower tricarboxylic acid cycle enzyme aconitase and higher protein carbonyls; in both, lower glycolytic enzyme enolase. Therefore in R6/2 striatum, lowered CMRO2may be attributed to a decrease in mitochondria while the cortical CMRO2decrease may result from constraints upstream in energetic pathways, suggesting regionally specific changes and possibly rates of metabolic impairment.
authors.affiliation: Department of Neuroscience.
authors.forename: Song
authors.initials: S
authors.lastname: Lou
authors.affiliation: Department of Neuroscience.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Lepak
authors.affiliation: Division of Biostatistics, School of Public Health.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Eberly
authors.affiliation: Department of Neuroscience.
authors.forename: Brian
authors.initials: B
authors.lastname: Roth
authors.affiliation: Center for MR Research, Department of Radiology, Medical School, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Weina
authors.initials: W
authors.lastname: Cui
authors.affiliation: Center for MR Research, Department of Radiology, Medical School, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Zhu
authors.affiliation: Center for MR Research, Department of Radiology, Medical School, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Gülin
authors.initials: G
authors.lastname: Öz
authors.affiliation: Department of Neuroscience dubin001@umn.edu.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Dubinsky
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004140:Dinitrophenols; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology
chemical_list: D004140:Dinitrophenols