Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondria are the most important intracellular source of reactive oxygen species and are protected against them by enzymatic and nonenzymatic antioxidants. Nevertheless, mitochondrial DNA (mtDNA) is subject to severe oxidative damage, and much more so than nuclear DNA (nDNA). Damage is indicated by the detection of various base modifications, particularly 8-hydroxydeoxyguanosine (8OHdG), which can lead to point mutations because of mispairing. MtDNA is also fragmented to some extent. Conceivably, such fragmentation relates to the deletions found in mtDNA. Several hypotheses suggest that defective mitochondria contribute to, or are responsible for, ageing. Recent observations indicate that mitochondria in an old organism differ in many respects from those in a young organism. Thus, with ageing there is an increased production of reactive oxygen species, a decrease in certain antioxidants, a decreased transcription, translation, and cytochrome oxidase content, and an increase in the extent of DNA modifications. Major unresolved questions concerning the role of mtDNA changes in ageing are addressed: is there a causal relationship; what is the true extent of DNA damage; what are significance and functional consequences of mtDNA oxidation; are reactive oxygen species the cause of the DNA modifications found in vivo; what is the relationship between DNA damage and alterations of RNAs and proteins? Future studies promise to clarify the possible causal relationship between mitochondrial dysfunction, reactive oxygen species production, mtDNA modifications, and ageing.
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PMID:Oxidative damage to mitochondrial DNA and its relationship to ageing. 764 20

The aim of this study is to elucidate effects of aging on mitochondrial function and mitochondrial DNA (mtDNA) in rat heart and liver. The activities of complex I and complex IV of heart mitochondria of rats aged 100 weeks decreased significantly by 31% and 22%, respectively, compared with those of rats aged 7 weeks. No significant changes were observed in these two parameters in rats aged 7 weeks and aged 55 weeks. There were no significant differences in the specific activities of complex II and complex III among the age groups of 7, 55, and 100 weeks. The mtDNA content decreased by 58% in rats aged 100 weeks compared with that in rats aged 7 weeks. Content of 8-hydroxydeoxyguanosine (8-OH-dG), an oxidative product of deoxyguanosine (dG), increased by 130% in rats aged 100 weeks compared with that in rats aged 7 weeks. No significant changes were observed in these parameters between rats aged 7 weeks and 55 weeks. In contrast to heart mtDNA, these age-dependent changes were not observed in liver mitochondria at rats aged up to 100 weeks. From our results, age-associated decline in mitochondrial function might play an important role in cell aging, particularly in postmitotic cells such as heart muscle, and accumulation of oxidative damage to mtDNA might be involved in this mechanism.
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PMID:Age-associated damage in mitochondrial function in rat hearts. 834 97

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

Regular resistance exercise increases muscle strength and induces muscle fibre hypertrophy in older adults. Although the underlying causes of aging remain unclear, like acute exercise, aging is associated with oxidative stress. In ageing, however, oxidative stress is closely associated with mitochondrial dysfunction as proposed by the mitochondrial theory of aging. The effect of regular resistance exercise upon mitochondrial function and oxidative stress in older adults is unknown. Twenty-eight older men and women (approximately 68.5+/-5.1 yr) performed whole-body resistance exercise training for 14 weeks. Muscle biopsies were taken before and 72 h following the last exercise bout from the vastus lateralis. Urine samples were also taken at the time of tissue collection. Resistance exercise training was associated with a decrease in 8-OHdG (Pre: 10783+/-5856, Post: 8897+/-4030 ng g(-1) creatinine; p<0.05). Protein content for CuZnSOD, MnSOD, and catalase, and enzyme activities for citrate synthase, mitochondrial ETC complex I+III, and complex II+III were not significantly different from baseline. However, complex IV activity was significantly higher after training as compared to before training (Pre: 2.2+/-0.5, Post: 2.9+/-0.9 micromol min(-1) g(-1)ww; p<0.05), as was the ratio of complex IV to complex I (Pre: 11.1+/-9.3, Post: 14.5+/-10.3; p<0.05). There were no apparent changes in normal mtDNA content or visible mtDNA deletion products as a function of training. These data suggest that regular resistance exercise decreases oxidative stress, but does not affect mtDNA. Moreover, increases in complex IV of the electron transport chain may have an indirect antioxidant effect in older adults and may improve function in daily activities.
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PMID:Resistance exercise training decreases oxidative damage to DNA and increases cytochrome oxidase activity in older adults. 1576 94

The present study elucidates a possible mechanism by which chronic organophosphate exposure (dichlorvos 6 mg/kg bw, s.c. for 12 weeks) causes neuronal degeneration. Mitochondria, as a primary site of cellular energy generation and oxygen consumption represent itself a likely target for organophosphate poisoning. Therefore, the objective of the current study was planned with an aim to investigate the effect of chronic dichlorvos exposure on mitochondrial calcium uptake, oxidative stress generation and its implication in the induction of neuronal apoptosis in rodent model. Mitochondrial preparation from dichlorvos (DDVP) treated rat brain demonstrated significant increase in mitochondrial Ca(2+) uptake (644.2 nmol/mg protein). Our results indicated decreased mitochondrial electron transfer activities of cytochrome oxidase (complex IV) along with altered mitochondrial complex I, and complex II activity, which might have resulted from elevated mitochondrial calcium uptake. The alterations in the mitochondrial calcium uptake and mitochondrial electron transfer enzyme activities in turn might have caused an increase in malondialdehyde, protein carbonyl and 8-hydroxydeoxyguanosine formation as a result of enhanced lipid peroxidation, and as well as protein and mtDNA oxidation. All this could have been because of enhanced oxidative stress, decreased GSH levels and also decreased Mn-SOD activity in the mitochondria isolated from dichlorvos treated rat brain. Thus, chronic organophosphate exposure has the potential to disrupt cellular antioxidant defense system which in turn triggers the release of cytochrome c from mitochondria to cytosol as well as caspase-3 activation in dichlorvos treated rat brain as revealed by immunoblotting experiments. Low-level long-term organophosphate exposure finally resulted in oligonucleosomal DNA fragmentation, a hallmark of apoptosis. These studies provide an evidence of impaired mitochondrial bioenergetics and apoptotic neuronal degeneration after chronic low-level exposure to dichlorvos.
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PMID:Impaired mitochondrial energy metabolism and neuronal apoptotic cell death after chronic dichlorvos (OP) exposure in rat brain. 1785 Aug 75

Exposure of arsenic (As) elevates reactive oxygen species (ROS) level, which is supposed to be a molecular mechanism of As neurotoxicity. Mitochondria are the major source of ROS. However, the mechanism of the ROS generation induced by As remains unclear. To provide target evidence for exploring the molecular mechanism of As-induced neurotoxicity, 8-hydroxy-2-deoxyguanosine (8-OHdG) as an oxidative damage biomarker was examined, and the critical gene expression profiles related to mitochondrial respiratory chain were analyzed by GeneChip in mice exposed to As(2)O(3) subchronically. Our results showed that immunoreactivity of 8-OHdG increased remarkably. Succinate dehydrogenase subunit A (Sdha), ubiquinol-cytochrome c oxidoreductase gene (Uqcr), cytochrome oxidase genes (Cox6a2, Cox17) and ATP Synthase genes (Atp5a1, Atp5g1, Atpif1) were down-regulated in brain cells of mice exposed to As. We further analyzed the influence of As on brain Sdha expression using Western blot method. The quantity of Sdha band and the corresponding succinate dehydrogenase (SDH) activity in the group exposed to 4ppm As(2)O(3) significantly decreased compared to the 1ppm or control group, agreeing well with the gene microarray result. These results indicate that subchronic exposure to As induces down-regulation of Sdha expression and inhibition of SDH activity in brain tissue. They also suggest that the Sdha as complex II subunit may be a molecular target for As in mitochondria. Furthermore, the intervening experiment showed that the coadministered antioxidants taurine or vitamin C scavenging ROS in vivo partly rescued Sdha expression. It implies that the increased level of ROS by As may also be a factor in the disrupting Sdha expression in brain tissue of mice exposed to As.
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PMID:Subchronic exposure to arsenic decreased Sdha expression in the brain of mice. 1942 48