Oxygen consumption deficit in Huntington disease mouse brain under metabolic stress

Song Lou, Victoria C. Lepak, Lynn E. Eberly, Brian Roth, Weina Cui, Xiao Hong Zhu, Gülin Öz, Janet M. Dubinsky

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


In vivo evidence for brain mitochondrial dysfunction in animal models of Huntington disease (HD) is scarce. We applied the novel 17O 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 CMRO2 in 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 CMRO2 of 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 CMRO2 in 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 CMRO2 equally 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 CMRO2 may be attributed to a decrease in mitochondria while the cortical CMRO2 decrease may result from constraints upstream in energetic pathways, suggesting regionally specific changes and possibly rates of metabolic impairment.

Original languageEnglish (US)
Pages (from-to)2813-2826
Number of pages14
JournalHuman molecular genetics
Issue number13
StatePublished - 2016

Bibliographical note

Publisher Copyright:
© The Author 2016. Published by Oxford University Press.


Dive into the research topics of 'Oxygen consumption deficit in Huntington disease mouse brain under metabolic stress'. Together they form a unique fingerprint.

Cite this