Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.9.3.1 (cytochrome oxidase)
8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the Huntington's disease (HD) gene defect has been identified, the structure and function of the abnormal gene product and the pathogenetic mechanisms involved in producing death of selective neuronal populations are not understood. Indirect evidence from several sources indicates that a defect of energy metabolism and consequent excitotoxicity are involved in HD. Toxin models of HD may be induced by 3-nitropropionic acid or malonate, both inhibitors of succinate dehydrogenase, complex II of the mitochondrial respiratory chain. We analyzed mitochondrial respiratory chain function in the caudate nucleus (n = 10) and platelets (n = 11) from patients with HD. In the caudate nucleus, severe defects of complexes II and III (53-59%, p < 0.0005) and a 32-38% (p < 0.01) deficiency of complex IV activity were demonstrated. No deficiencies were found in platelet mitochondrial function. The mitochondrial defect identified in HD caudate parallels that induced by HD neurotoxin models and further supports the role of abnormal energy metabolism in HD. The relationship of the mitochondrial defect to the role of huntingtin is not known.
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PMID:Mitochondrial defect in Huntington's disease caudate nucleus. 860 59

Rapid advances are being made in our understanding of the pathogenesis of neurodegenerative diseases, particularly those in which specific DNA mutations have been identified. beta-amyloid has been shown to induce free radical formation both directly and via an effect on endothelial function. There is presuasive evidence for cytochrome oxidase dysfunction with oxidative stress and damage in the brains of patients with Alzheimer's disease. The confirmation of the complex II inhibitor 3-nitropropionic acid as a toxin model for Huntington's disease, together with the demonstration of reduced mitochondrial function in Huntington's disease caudate, supports the proposition that mutant huntingtin may exert its effect through an abnormality of energy metabolism.
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PMID:Oxidative stress and mitochondrial dysfunction in neurodegeneration. 885 82

The etiology of the selective neuronal death that occurs in Huntington's disease (HD) is unknown. Several lines of evidence implicate the involvement of energetic defects and oxidative damage in the disease process, including a recent study that demonstrated an interaction between huntingtin protein and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using spectrophotometric assays in postmortem brain tissue, we found evidence of impaired oxidative phosphorylation enzyme activities restricted to the basal ganglia in HD brain, while enzyme activities were unaltered in three regions relatively spared by HD pathology (frontal cortex, parietal cortex, and cerebellum). Citrate synthase-corrected complex II-III activity was markedly reduced in both HD caudate (-29%) and putamen (-67%), and complex IV activity was reduced in HD putamen (-62%). Complex I and GAPDH activities were unaltered in all regions examined. We also measured levels of the oxidative damage product 8-hydroxydeoxyguanosine (OH8dG) in nuclear DNA, and superoxide dismutase (SOD) activity. OH8dG levels were significantly increased in HD caudate. Cytosolic SOD activity was slightly reduced in HD parietal cortex and cerebellum, whereas particulate SOD activity was unaltered in these regions. These results further support a role for metabolic dysfunction and oxidative damage in the pathogenesis of HD.
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PMID:Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia. 915 27

A potential pivotal role for mitochondrial dysfunction in neurodegenerative diseases is gaining increasing acceptance. Mitochondrial dysfunction leads to a number of deleterious consequences including impaired calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and secondary excitotoxicity. Neurodegenerative diseases of widely disparate genetic etiologies may share mitochondrial dysfunction as a final common pathway. Recent studies using cybrid cell lines suggest that sporadic Alzheimer's disease is associated with a deficiency of cytochrome oxidase. Friedreich's ataxia is caused by an expanded GAA repeat resulting in dysfunction of frataxin, a nuclear encoded mitochondrial protein involved in mitochondrial iron transport. This results in increased mitochondrial iron and oxidative damage. Familial amyotrophic lateral sclerosis is associated with point mutations in superoxide dismutase, which may lead to increased generation of free radicals and thereby contribute to mitochondrial dysfunction. Huntington's disease (HD) is caused by an expanded CAG repeat in an unknown protein termed huntingtin. The means by which this leads to energy impairment is unclear, however studies in both HD patients and a transgenic mouse model show evidence of bioenergetic defects. Mitochondrial dysfunction leads to oxidative damage which is well documented in several neurodegenerative diseases. Therapeutic approaches include methods to buffer intracellular ATP and to scavenge free radicals.
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PMID:Mitochondrial dysfunction in neurodegenerative diseases. 971 10

The physiological role of huntingtin and the mechanisms by which the expanded CAG repeat in ITI5 and its polyglutamine stretch in mutant huntingtin induce Huntington's disease (HD) are unknown. Several techniques have now demonstrated abnormal metabolism in HD brain; direct measurement of respiratory chain enzyme activities has shown severe deficiency of complex II/III and a milder defect of complex IV. We confirm that these abnormalities appear to be confined to the striatum within the HD brain. Analysis of complex II/III activity in HD fibroblasts was normal, despite expression of mutant huntingtin. Although glyceraldehyde 3-phosphate dehydrogenase (a huntingtin binding protein) activity was normal in all areas studied, aconitase activity was decreased to 8% in HD caudate, 27% in putamen, and 52% in cerebral cortex, but normal in HD cerebellum and fibroblasts. We have demonstrated that although complexes II and III are those parts of the respiratory chain most vulnerable to inhibition in the presence of a nitric oxide (NO*) generator, aconitase activity was even more sensitive to inhibition. The pattern of these enzyme deficiencies and their parallel to the anatomical distribution of HD pathology support an important role for NO* and excitotoxicity in HD pathogenesis. Furthermore, based on the biochemical defects we have described, we suggest that NO* generation produces a graded response, with aconitase inhibition followed by complex II/III inhibition and the initiation of a self-amplifying cycle of free radical generation and aconitase inhibition, which results in severe ATP depletion. We propose that these events are important in determining neuronal cell death and are critical steps in the pathogenesis of HD.
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PMID:Biochemical abnormalities and excitotoxicity in Huntington's disease brain. 989 73

Huntington's disease is a progressive neurodegenerative disease caused by an abnormally expanded (>36) CAG repeat within the ITI5 gene encoding a widely expressed 349-kd protein, huntingtin. The medium spiny neurons of the caudate preferentially degenerate in Huntington's disease, with the presence of neuronal intranuclear inclusions. Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease; the recently described mitochondrial respiratory chain and aconitase defects in Huntington's disease brain are consistent with this hypothesis. A transgenic mouse model (R6/2) of Huntington's disease develops a movement disorder, muscle wasting, and premature death at about 14 to 16 weeks. Selective neuronal death in these mice is not seen until 14 weeks. Biochemical analysis of R6/2 mouse brain at 12 weeks demonstrated a significant reduction in aconitase and mitochondrial complex IV activities in the striatum and a decrease in complex IV activity in the cerebral cortex. Increased immunostaining for inducible nitric oxide synthase and nitrotyrosine was seen in the transgenic mouse model but not control mouse brains. These results extend the parallels between Huntington's disease and the transgenic mouse model to biochemical events and suggest complex IV deficiency and elevated nitric oxide and superoxide radical generation precede neuronal death in the R6/2 mouse and contribute to pathogenesis.
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PMID:Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. 1063 4

There is significant evidence that energy production impairment and mitochondrial dysfunction play a role in the pathogenesis of Huntington disease. Nonetheless, the specific mitochondrial defects due to the presence of mutant huntingtin have not been fully elucidated. To determine the effects of mutant huntingtin on mitochondrial energy production, a thorough analysis of respiration, ATP production, and functioning of the respiratory complexes was carried out in clonal striatal cells established from Hdh(Q7) (wild-type) and Hdh(Q111) (mutant huntingtin knock-in) mouse embryos. Mitochondrial respiration and ATP production were significantly reduced in the mutant striatal cells compared with the wild-type cells when either glutamate/malate or succinate was used as the substrate. However, mitochondrial respiration was similar in the two cell lines when the artificial electron donor TMPD/ascorbate, which feeds into complex IV, was used as the substrate. The attenuation of mitochondrial respiration and ATP production when either glutamate/malate or succinate was used as the substrate was not due to impairment of the respiratory complexes, because their activities were equivalent in both cell lines. Intriguingly, in the striatum of presymptomatic and pathological grade 1 Huntington disease cases there is also no impairment of mitochondrial complexes I-IV (Guidetti, P., Charles, V., Chen, E. Y., Reddy, P. H., Kordower, J. H., Whetsell, W. O., Jr., Schwarcz, R., and Tagle, D. A. (2001) Exp. Neurol. 169, 340-350). To our knowledge, this is the first comprehensive analysis of the effects of physiological levels of mutant huntingtin on mitochondrial respiratory function within an appropriate cellular context. These findings demonstrate that the presence of mutant huntingtin impairs mitochondrial ATP production through one or more mechanisms that do not directly affect the function of the respiration complexes.
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PMID:Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. 1598 33

We present evidence for a specific role of p53 in the mitochondria-associated cellular dysfunction and behavioral abnormalities of Huntington's disease (HD). Mutant huntingtin (mHtt) with expanded polyglutamine (polyQ) binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity in neuronal cultures. The augmentation is specific, as it occurs with mHtt but not mutant ataxin-1 with expanded polyQ. p53 levels are also increased in the brains of mHtt transgenic (mHtt-Tg) mice and HD patients. Perturbation of p53 by pifithrin-alpha, RNA interference, or genetic deletion prevents mitochondrial membrane depolarization and cytotoxicity in HD cells, as well as the decreased respiratory complex IV activity of mHtt-Tg mice. Genetic deletion of p53 suppresses neurodegeneration in mHtt-Tg flies and neurobehavioral abnormalities of mHtt-Tg mice. Our findings suggest that p53 links nuclear and mitochondrial pathologies characteristic of HD.
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PMID:p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. 1599 41

Mitochondrial abnormalities represent a major cytopathology in Huntington's disease (HD), a fatal neurodegenerative disease caused by CAG repeat expansions in the gene encoding huntingtin (Htt). In the present study, we investigated whether defects in the mitochondrial respiratory function are consequences of the expression of mutant Htt or they promote the formation of Htt aggregates. To take advantage of existing mitochondrial DNA mutants, we developed human osteosarcoma 143B cells expressing mutant Htt in an inducible manner and found that cells expressing mutant Htt but not wild-type Htt exhibited a reduced activity of complex III and an increased activity of complex IV. Conversely, pharmacological treatments that inhibited complex III activity significantly promoted the formation of Htt aggregates. This complex III-mediated modulation of Htt aggregates was also observed in a neuronal progenitor RN33B cell line transduced by lentivirus carrying mutant Htt. This effect of complex III inhibition on the Htt aggregates appeared to be mediated by the inhibition of proteasome activity, but not by ATP depletion or production of reactive oxygen species. Accordingly, complex III mutant cells also showed decreased proteasome activity. These results suggest the presence of a feedback system connecting the mitochondrial respiratory complex III and the production of Htt aggregates. Our results suggest that therapeutic interventions targeting complex III and/or proteasome could ameliorate the progress of HD.
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PMID:Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates. 1735 14

The purpose of our study was to determine the relationship between mutant huntingtin (Htt) and mitochondrial dynamics in the progression of Huntington's disease (HD). We measured the mRNA levels of electron transport chain genes, and mitochondrial structural genes, Drp1 (dynamin-related protein 1), Fis1 (fission 1), Mfn1 (mitofusin 1), Mfn2 (mitofusin 2), Opa1 (optric atrophy 1), Tomm40 (translocase of outermembrane 40) and CypD (cyclophilin D) in grade III and grade IV HD patients and controls. The mutant Htt oligomers and the mitochondrial structural proteins were quantified in the striatum and frontal cortex of HD patients. Changes in expressions of the electron transport chain genes were found in HD patients and may represent a compensatory response to mitochondrial damage caused by mutant Htt. Increased expression of Drp1 and Fis1 and decreased expression of Mfn1, Mfn2, Opa1 and Tomm40 were found in HD patients relative to the controls. CypD was upregulated in HD patients, and this upregulation increased as HD progressed. Significantly increased immunoreactivity of 8-hydroxy-guanosine was found in the cortical specimens from stage III and IV HD patients relative to controls, suggesting increased oxidative DNA damage in HD patients. In contrast, significantly decreased immunoreactivities of cytochrome oxidase 1 and cytochrome b were found in HD patients relative to controls, indicating a loss of mitochondrial function in HD patients. Immunoblotting analysis revealed 15, 25 and 50 kDa mutant Htt oligomers in the brain specimens of HD patients. All oligomeric forms of mutant Htt were significantly increased in the cortical tissues of HD patients, and mutant Htt oligomers were found in the nucleus and in mitochondria. The increase in Drp1, Fis1 and CypD and the decrease in Mfn1 and Mfn2 may be responsible for abnormal mitochondrial dynamics that we found in the cortex of HD patients, and may contribute to neuronal damage in HD patients. The presence of mutant Htt oligomers in the nucleus of HD neurons and in mitochondria may disrupt neuronal functions. Based on these findings, we propose that mutant Htt in association with mitochondria imbalance and mitochondrial dynamics impairs axonal transport of mitochondria, decreases mitochondrial function and damages neurons in affected brain regions of HD patients.
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PMID:Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage. 2146 18


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