Selective defect of in vivo glycolysis in early Huntington's disease striatum

Abstract

Activity of complexes II, III, and IV of the mitochondrial electron transport system (ETS) is reduced in postmortem Huntington's disease (HD) striatum, suggesting that reduced cerebral oxidative phosphorylation may be important in the pathogenesis of neuronal death. We investigated mitochondrial oxidative metabolism in vivo in the striatum of 20 participants with early, genetically proven HD and 15 age-matched normal controls by direct measurements of the molar ratio of cerebral oxygen metabolism to cerebral glucose metabolism (CMRO2/CMRglc) with positron emission tomography. There was a significant increase in striatal CMRO2/CMRglc in HD rather than the decrease characteristic of defects in mitochondrial oxidative metabolism (6.0 ؎ 1.6 vs. 5.1 ؎ 0.9, P ‫؍‬ 0.04). CMRO2 was not different from controls (126 ؎ 37 vs. 134 ؎ 31 mol 100 g ؊1 min ؊1 , P ‫؍‬ 0.49), whereas CMRglc was decreased (21.6 ؎ 6.1 vs. 26.4 ؎ 4.6 mol 100 g ؊1 min ؊1 , P ‫؍‬ 0.01). Striatal volume was decreased as well (13.9 ؎ 3.5 vs. 17.6 ؎ 2.0 ml, P ‫؍‬ 0.001). Increased striatal CMRO2/CMRglc with unchanged CMRO2 is inconsistent with a defect in mitochondrial oxidative phosphorylation due to reduced activity of the mitochondrial ETS. Because HD pathology was already manifest by striatal atrophy, deficient energy production due to a reduced activity of the mitochondrial ETS is not important in the mechanism of neuronal death in early HD. Because glycolytic metabolism is predominantly astrocytic, the selective reduction in striatal CMRglc raises the possibility that astrocyte dysfunction may be involved in the pathogenesis of HD.cerebral metabolism ͉ mitochondria ͉ oxidative phosphorylation ͉ basal ganglia H untington's disease (HD) is a degenerative neurological disease that is manifested by abnormal involuntary movements, psychiatric disorders, and dementia. It has a variable age at onset and progresses slowly to death 15-25 years after symptoms develop. HD is neuropathologically characterized by early selective loss of medium spiny neurons in striatum (caudate and putamen) with later neuronal loss in cortex, globus pallidus, and other structures. Although it is now known that an expansion of the triple repeat CAG in the IT15 gene on chromosome 4 leads to production of an abnormal polyglutamine string on the huntingtin protein, it is still unclear how this leads to selective neuronal cell death (1). In postmortem specimens from the striatum of patients with HD, reduced activity of the mitochondrial electron transport system (ETS) (29-76% decreases in complexes II and III and 30-62% decreases in complex IV) has been measured in vitro, although these findings have not been universal (2-6). These findings and the correlative effects of mitochondrial toxins in producing striatal neuronal loss in animal models suggest that excitotoxicity triggered by reduced ATP production as a consequence of impaired mitochondrial oxidative phosphorylation may be an important mechanism for neuronal death in HD (7). Alternatively, these mitochondrial changes may be ...

Morning-evening variation in human brain metabolism and memory circuits

“…In these individuals blood flow was 54 ml·g Ϫ1 ·min Ϫ1 in the evening before sleep, a value significantly higher (17%) than that obtained the following morning. However, it should be noted that the value they obtained in the evening was within the range of normal values obtained in humans without regard to the time of day (e.g., see Kety and Schmidt 1948;Powers et al 2007;Raichle et al 1970). The authors suggested this difference could be due to increases in blood flow due to sleep deprivation or a decrease brought about by intervening "recovery sleep" (or both).…”

“…Traditionally, it has been tacitly assumed by most that the consumption of glucose and oxygen represents the brain's need for energy without consideration of possible additional roles. However, we know that glucose consumption exceeds that needed for oxidative phosphorylation by about 15% in the resting adult human (Powers et al 2007;Raichle et al 1970). This has traditionally been referred to as aerobic glycolysis (i.e., glucose consumption occurring in excess of that needed for oxidative phosphorylation in the presence of adequate tissue oxygenation).…”

Bioenergetic dysfunction in Huntington's disease human cybrids

“…Modified glycolytic energy metabolism has been described in HD patients, both in central and in peripheral tissues, as suggested by high levels of lactate in the striatum (Jenkins et al, 1993) and in the cortex (Jenkins et al, 1993;Koroshetz et al, 1997), increased lactate/ pyruvate ratio in the CSF (Koroshetz et al, 1997), but decreased astrocytic glucose metabolism in the striatum with preserved oxygen metabolism in early symptomatic HD patients (Powers et al, 2007b). Moreover, the activity of G6PD, a key enzyme of the pentose phosphate pathway, was decreased in HD cybrids, suggesting that glucose metabolization occurs through the glycolytic pathway.…”

“…HD patients present high levels of lactate in both the striatum (Jenkins et al, 1993) and cortex (Jenkins et al, 1993;Koroshetz et al, 1997), and increased lactate/pyruvate ratio in the cerebrospinal fluid (CSF) (Koroshetz et al, 1997). Striatal glucose metabolism was also shown to be decreased, whereas oxygen metabolism is preserved in early symptomatic HD patients (Powers et al, 2007b). Moreover, increased glucose metabolism and ATP levels were found in brain tissue of HD N171-82Q mice, suggesting that the neuronal damage in HD tissue may be associated with increased energy metabolism at the tissue level, leading to modified levels of various intermediary metabolites (Olah et al, 2008).…”

Dissociated Expression of Mitochondrial and Cytosolic Creatine Kinases in the Human Brain: A New Perspective on the Role of Creatine in Brain Energy Metabolism

“…During HD, an increased ratio of the cerebral metabolic rate of oxygen consumption to glucose consumption is an indication of an impairment in glycolysis. 39 Furthermore, the selective inhibition of glycolysis with iodoacetate increases the susceptibility of medium spiny neurons to excitotoxic cell death in the R6/2 transgenic mouse model of HD. 40 All of these properties seen in medium spiny neurons point to a neuron type that is energetically unique in the brain: a strong dependence on oxidative metabolism and glycolysis to cope with the high energy demands as a result of its connectivity.…”