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 novel O magnetic resonance spectroscopy (MRS) technique on R6/2 mice to directly determine rates of oxygen consumption (CMRO) and assess mitochondrial function in vivo Basal respiration and maximal CMRO 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 CMRO 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 CMRO 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 CMRO 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 CMRO may be attributed to a decrease in mitochondria while the cortical CMRO decrease may result from constraints upstream in energetic pathways, suggesting regionally specific changes and possibly rates of metabolic impairment.

Expression of mutant exon 1 huntingtin fragments in human neural stem cells and neurons causes inclusion formation and mitochondrial dysfunction

“…Cellular respiratory deficits have been reported previously in HD cell models, including primary cultures derived from mouse R6/2 and rat BACHD models, 47‐50 but the effects were inconsistent. Other reports using the methods outlined here show no differences in OCR or ATP production in isolated rodent neurons 51 .…”

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

“…Inhibition of oxidative phosphorylation with oligomycin resulted in a similar decrease in respiration, suggesting similar phosphorylation capacity and coupling of oxidative phosphorylation in HD and wild-type mice. Yet, after injection of the uncoupler 2,4-DNP, the authors found a negligible (about 15%), but statistically significant, decrease in respiratory responses in both striatum and cortex of R6/2 mice compared with respiratory responses of corresponding brain tissues in wild-type animals (Lou et al, 2016). The physiological significance of this difference is not evident but it is clear that such conditions (2,4-DNP-induced stimulation) do not take place in real life.…”

“…However, in vivo measurements of brain respiratory activity may further enhance our understanding of potential defects in oxidative metabolism in HD. A recent paper by Lou et al described elegant experiments with the use of 17 O magnetic resonance spectroscopy aimed at assessing cerebral mitochondrial respiratory activity in R6/2 mice in vivo (Lou et al, 2016). In this study, the authors did not find a difference in basal striatal oxygen consumption rate in symptomatic R6/2 mice at rest.…”

In vivo 17 O MRS imaging – Quantitative assessment of regional oxygen consumption and perfusion rates in living brain

“…This novel 17 O-MR based CMRO 2 imaging technique has been successfully applied to Huntington disease mouse brains and used as a metabolic imaging tool to assess the mitochondrial function in diseased brain in vivo by directly determining the cerebral oxygen consumption deficit under metabolic stress [51]. It is expected that more studies of this kind will be forthcoming once the research community recognizes the promise of this new technology.…”

“…High/ultrahigh field scanners are employed in the 17 O MRS imaging studies due to the advantages in gain of sensitivity. It has been shown that a few millimeter spatial resolution in preclinical studies [26, 34, 35, 37–39, 48, 50, 51] and close to a centimeter in human studies [32, 45, 53] with ~10–15 sec temporal resolution can be reached with B 0 ≥ 7T. Relatively lower resolutions are expected with lower field magnets, e.g., a 3T clinical scanner, or when large volume coils are employed [30, 36, 54, 56].…”