Regional Mitochondrial Respiratory Activity in Huntington's Disease Brain

Brennan, William A.; Bird, Edward D.; Aprille, June R.

doi:10.1111/j.1471-4159.1985.tb07192.x

Cited by 241 publications

(138 citation statements)

References 21 publications

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“…In the context of PolyQ disorders, studies on HD animal and cultured cell models have linked defective mitochondrial bioenergetics to HD pathogenesis. In HD patients, reductions in the activities of the mitochondrial ETC complexes II, III and IV have been observed in the postmortem brain (Brennan et al, 1985;Browne et al, 1997;Gu et al, 1996). Similar observations involving dysfunctional respiratory chain complexes and increased oxidative stress has been made in the pathology associated with the SCA2, SCA3, and SCA12…”

Section: Discussionsupporting

confidence: 64%

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

Stucki

Ruegsegger

Steiner

et al. 2016

Free Radical Biology and Medicine

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Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ, Free Radical Biology and Medicine, http://dx.doi.org/10.1016/j.freeradbiomed.2016.07.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Discussionsupporting

confidence: 64%

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

Stucki

Ruegsegger

Steiner

et al. 2016

Free Radical Biology and Medicine

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“…These white matter effects will worsen with caudate and putaminal atrophy and, thus, could potentially result in a measured reduction in striatal CMRO 2 in HD when none actually exists. However, because the partial volume effect of surrounding white matter will be the same for CMRO 2 and CMRglc, the use of the ratio eliminates this problem. The CMRO 2 method that we have used has been validated for quantitative accuracy in nonhuman primates across a wide range of CMRO 2 (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…These results are unexpected in light of the reports of reduced mitochondrial ETS activity in postmortem striatal tissue from patients with HD. These postmortem studies measured reduced activity of mitochondrial ETS activity in gross tissue samples from both caudate and putamen indicating that, even if these defects are restricted to only a certain fraction of striatal cells, they are of sufficient magnitude to be detected in assays of the structures as a whole (2)(3)(4)(5)27). Our finding of preserved mitochondrial oxidative metabolism early in HD when neuronal loss is already manifest by striatal atrophy indicates that any defects in ATP production due to striatal ETS activity are either insufficient to impair oxidative phosphorylation or are not present early in the course of the disease (6, 9).…”

Section: Discussionmentioning

confidence: 99%

“…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)(3)(4)(5)(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).…”

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confidence: 99%

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

Powers

Videen

Markham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

152

153

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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 ...

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“…Mitochondrial deficiencies, including reduced overall respiration and reduced activities of complex II, III, and IV, have been measured in the striatum of postmortem HD brains (14,15). Similarly, reduced mitochondrial activity has been observed in at least one genetic mouse model of HD (16), and enhancement of electron transport by coenzyme Q10 is effective in genetic models (17)(18)(19)(20).…”

mentioning

confidence: 99%

Protection from mitochondrial complex II inhibitionin vitroandin vivoby Nrf2-mediated transcription

Calkins

Jakel

Johnson

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

238

206

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Complex II inhibitors 3-nitropropionic acid (3NP) and malonate cause striatal damage reminiscent of Huntington's disease and have been shown to involve oxidative stress in their pathogenesis. Because nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent transcriptional activation by means of the antioxidant response element is known to coordinate the up-regulation of cytoprotective genes involved in combating oxidative stress, we investigated the significance of Nrf2 in complex II-induced toxicity. We found that Nrf2-deficient cells and Nrf2 knockout mice are significantly more vulnerable to malonate and 3NP and demonstrate increased antioxidant response element (ARE)-regulated transcription mediated by astrocytes. Furthermore, ARE preactivation by means of intrastriatal transplantation of Nrf2-overexpressing astrocytes before lesioning conferred dramatic protection against complex II inhibition. These observations implicate Nrf2 as an essential inducible factor in the protection against complex II inhibitor-mediated neurotoxicity. These data also introduce Nrf2-mediated ARE transcription as a potential target of preventative therapy in neurodegenerative disorders such as Huntington's disease.3-nitropropionic acid ͉ antioxidant response element ͉ astrocytes ͉ malonate M itochondrial complex II inhibition with 3-nitropropionic acid (3NP) or malonate produces a characteristic striatal degeneration similar to that seen in Huntington's disease (HD) (1, 2). HD is an autosomal dominant neurodegenerative disorder that results from a polyglutamine repeat expansion in the first exon of the huntingtin gene (3). Hallmarks of the genetic disease include severe degeneration of striatal medium spiny neurons and progressive choreiform movements (4, 5). Similar behavioral deficits and selective damage to the medium spiny neurons of the striatum with sparing of the aspiny neurons are seen after complex II inhibition (6-10).Furthermore, there is developing evidence that HD pathogenesis involves mitochondrial dysfunction, excitotoxicity, and subsequent reactive oxygen species (ROS) production (11-13). Mitochondrial deficiencies, including reduced overall respiration and reduced activities of complex II, III, and IV, have been measured in the striatum of postmortem HD brains (14,15). Similarly, reduced mitochondrial activity has been observed in at least one genetic mouse model of HD (16), and enhancement of electron transport by coenzyme Q10 is effective in genetic models (17)(18)(19)(20). HD patients also display increased ROS production in red blood cells and the striatum (21-24), which is reflected in in vitro and genetic mouse models of HD (18,(25)(26)(27).Complex II inhibitors generate ROS (26, 27) as a direct consequence of disruption of the electron transport chain and excitotoxicity by means of calcium influx through the N-methyl-D-aspartate receptor (28-30). Additionally, the high concentration of striatal dopamine may contribute to ROS production and exacerbate the damage caused by complex II inhibition (31). Stri...

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Regional Mitochondrial Respiratory Activity in Huntington's Disease Brain

Cited by 241 publications

References 21 publications

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

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

Protection from mitochondrial complex II inhibitionin vitroandin vivoby Nrf2-mediated transcription

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