Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00369 (ROS)
 19,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitochondrial rate of oxygen radical (ROS) production is negatively correlated with maximum life span potential (MLSP) in mammals following the rate of living theory. In order to know if this relationship is more than circumstantial, homeothermic vertebrates with MLSP different from that predicted by the body size and metabolic rate of the majority of mammals (like birds and primates) must be studied. Birds are unique because they combine a high rate of basal oxygen consumption with a high MLSP. Heart, brain, and lung mitochondrial ROS production and free radical leak (percent of total electron flow directed to ROS production) are lower in three species of birds of different orders than in mammals of similar body size and metabolic rate. This suggests that the capacity to show a low rate of ROS production is a general characteristic of birds. Using substrates and inhibitors specific for different segments of the respiratory chain, the main ROS generator site (responsible for those bird-mammalian differences) in state 4 has been localized at complexes I and III in heart mitochondria and only at complex I in nonsynaptic brain mitochondria. In state 3, complex I is the only generator in both tissues. The results also suggest that the iron-sulphur centers are the ROS generators of complex I. A general mechanism that allows pigeon mitochondria to show a low rate of ROS production can be the capacity to maintain a low degree of reduction of the ROS generator site. In heart mitochondria, this is supplemented with a low rate of oxygen consumption physiologically compensated with a comparatively higher heart size. A low rate of free radical production near DNA, together with a high rate of DNA repair, can be responsible for the slow rate of accumulation of DNA damage and thus the slow aging rate of longevous animals.
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PMID:Mitochondrial free radical production and aging in mammals and birds. 992 33

The phosphatidylinositol (PI)-3 kinase-Akt/PKB survival pathway protects neurons from apoptosis caused by diverse stress stimuli. However, its protective effect against neurotoxins that produce oxidative stress and neurodegeneration has not been investigated. We analyzed the effect of this pathway on the action of the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Overexpression of a membrane-targeted, N-myristylated fusion protein of enhanced green fluorescence protein (EGFP) and mouse Akt1 attenuated the apoptotic effect of the neurotoxin in PC12 cells. This effect was not due to protection of mitochondrial complex I activity or restoration of energy charge. Following MPP+-treatment, myr-EGFP-Akt1-transfected cells exhibited an unaltered mitochondrial membrane potential and lower ROS levels than control cells. These results provide a new site of action of Akt/PKB at the level of the oxidative detoxifying cell machinery and suggest that this effect may be responsible in part for the resistance of myr-EGFP-Akt1-expressing cells to oxidative stress and MPP+-induced apoptosis.
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PMID:Akt1/PKBalpha protects PC12 cells against the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium and reduces the levels of oxygen-free radicals. 1116 70

Oxygen free radicals (ROS) of mitochondrial origin seem to be involved in aging. Whereas in other tissues complexes I or III of the respiratory chain contain the ROS generators, in this study we find that rat liver mitochondria generate oxygen radicals at complexes I, II, and III. Short-term (6 weeks) caloric restriction significantly decreased H2O2 production in rat liver mitochondria. This decrease in ROS production was located at complex I because it occurred with complex I-linked substrates (pyruvate/malate), but did not reach statistical significance with the complex II-linked substrate succinate. The mechanism responsible for the lowered ROS production was not a decrease in oxygen consumption. Instead, the mitochondria of caloric-restricted animals released less ROS per unit electron flow. This was due to a decrease in the degree of reduction of the complex I generator. Furthermore, oxidative damage to mitochondrial and nuclear DNA was also decreased in the liver by short-term caloric restriction. The results agree with the idea that caloric restriction delays aging, at least in part, by decreasing the rate of mitochondrial ROS generation and thus the rate of attack to molecules, like DNA, highly relevant for the accumulation of age-dependent changes.
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PMID:Effect of short-term caloric restriction on H2O2 production and oxidative DNA damage in rat liver mitochondria and location of the free radical source. 1171 Aug 4

The effect of long-term caloric restriction and aging on the rates of mitochondrial H2O2 production and oxygen consumption as well as on oxidative damage to nuclear (nDNA) and mitochondrial DNA (mtDNA) was studied in rat liver tissue. Long-term caloric restriction significantly decreased H2O2 production of rat liver mitochondria (47% reduction) and significantly reduced oxidative damage to mtDNA (46% reduction) with no changes in nDNA. The decrease in ROS production was located at complex I because it only took place with complex I-linked substrates (pyruvate/malate) but not with complex II-linked substrates (succinate). The mechanism responsible for that decrease in ROS production was not a decrease in mitochondrial oxygen consumption because it did not change after long-term restriction. Instead, the caloric restricted mitochondria released less ROS per unit electron flow, due to a decrease in the reduction degree of the complex I generator. On the other hand, increased ROS production with aging in state 3 was observed in succinate-supplemented mitochondria because old control animals were unable to suppress H2O2 production during the energy transition from state 4 to state 3. The levels of 8-oxodG in mtDNA increased with age in old animals and this increase was abolished by caloric restriction. These results support the idea that caloric restriction reduces the aging rate at least in part by decreasing the rate of mitochondrial ROS production and so, the rate of oxidative attack to biological macromolecules like mtDNA.
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PMID:Influence of aging and long-term caloric restriction on oxygen radical generation and oxidative DNA damage in rat liver mitochondria. 1197 89

The clinical, biochemical and genetic features of Leber's hereditary optic neuropathy (LHON) are reviewed. The etiology of LHON is complex, but the primary risk factor is a mutation in one of the seven mitochondrial genes that encode subunits of respiratory chain complex I. The pathogenesis of LHON is not yet understood, but one plausible model is that increased or altered mitochondrial ROS production renders the retinal ganglion cells vulnerable to apoptotic cell death. In addition to LHON, there are a large number of other optic nerve degenerative disorders including autosomal dominant optic atrophy, the toxic/nutritional optic neuropathies and glaucoma. A review of the recent scientific literature suggests that these disorders also involve mitochondrial dysfunction or altered mitochondrial signaling pathways in their pathogenesis. This mitochondrial link provides new avenues of experimental investigation to these major causes of loss of vision.
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PMID:LHON and other optic nerve atrophies: the mitochondrial connection. 1287 32

Dependence on mitochondrial membrane potential (deltapsim) of hydrogen peroxide formation of in situ mitochondria in response to inhibition of complex I or III was studied in synaptosomes. Blockage of electron flow through complex I by rotenone or that through complex III by antimycin resulted in an increase in the rate of H2O2 generation as measured with the Amplex red assay. Membrane potential of mitochondria was dissipated by either FCCP (250 nM) or DNP (50 microM) and then the rate of H2O2 production was followed. Neither of the uncouplers had a significant effect on the rate of H2O2 production induced by rotenone or antimycin. Inhibition of the F0F1-ATPase by oligomycin, which also eliminates deltapsim in the presence of rotenone and antimycin, respectively, was also without effect on the ROS formation induced by rotenone and only slightly reduced the antimycin-induced H2O2 production. These results indicate that ROS generation of in situ mitochondria in nerve terminals in response to inhibition of complex I or complex III is independent of deltapsim. In addition, we detected a significant antimycin-induced H2O2 production when the flow of electrons through complex I was inhibited by rotenone, indicating that the respiratory chain of in situ mitochondria in synaptosomes has a substantial electron influx distal from the rotenone site, which could contribute to ROS generation when the complex III is inhibited.
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PMID:The production of reactive oxygen species in intact isolated nerve terminals is independent of the mitochondrial membrane potential. 1457 Apr 3

Mitochondria produce ROS (reactive oxygen species) as a by-product of aerobic respiration. Several studies in mammals and birds suggest that the most physiologically relevant ROS production is from complex I following reverse electron flow, and is highly sensitive to membrane potential. A study of Drosophila mitochondria respiring glycerol 3-phosphate revealed that membrane potential-sensitive ROS production from complex I following reverse electron flow was on the matrix side of the inner membrane. A 10 mV decrease in membrane potential was enough to abolish around 70% of the ROS produced by complex I under these conditions. Another important ROS generator in this model, glycerol-3-phosphate dehydrogenase, produced ROS mostly to the cytosolic side; this ROS production was totally insensitive to a small decrease in membrane potential (10 mV). Thus mild uncoupling may be particularly significant for ROS production from complex I on the matrix side of the mitochondrial inner membrane.
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PMID:Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling. 1464 Oct 47

A mutation in a subunit of complex I of the mitochondrial electron transport chain (gas-1) causes Caenorhabditis elegans to be hypersensitive to volatile anesthetics and oxygen as well as shortening lifespan. We hypothesized that changes in mitochondrial respiration or reactive oxygen species production cause these changes. Therefore, we compared gas-1 to other mitochondrial mutants to identify the relative importance of these two aspects of mitochondrial function in determining longevity. Lifespans of gas-1 and mev-1 were decreased compared with N2, while that of clk-1 was increased. Rates of oxidative phosphorylation were decreased in all three mutants, but the ROS damage was decreased only in clk-1. Suppressors of gas-1 increased rates of oxidative phosphorylation, decreased oxidative damage to mitochondrial proteins and increased lifespan. Two strains containing combinations of mutations predicted to have very decreased complex I function, had unexpectedly long lifespans. We conclude that mitochondrial changes in lifespan appear to be mediated primarily by changes in oxidative damage rather than by changes in rates of oxidative phosphorylation. In contrast, the effects of mitochondrial changes on anesthetic sensitivity appear to be mediated by both altered respiration and oxidative damage.
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PMID:The effects of complex I function and oxidative damage on lifespan and anesthetic sensitivity in Caenorhabditis elegans. 1517 35

Dihydrocalcein (H2-calcein) is recommended as a superior probe for intracellular radical (ROS) detection as different to dichlorodihydrofluorescein (H2-DCF), its oxidation product calcein is thought not to leak out of cells. We determined whether H2-calcein is a useful tool to measure ROS in vascular smooth muscle cells. In vitro, both compounds were oxidized by peroxynitrite, hydroxyl radicals and peroxidase, but not hydrogen peroxide or nitric oxide. The intracellular half-life of calcein was several hours whereas that of DCF was approximately 5 min. Intracellular ROS, as generated by the angiotensin II (Ang II)-activated NADPH oxidase, did not increase the oxidation of H2-calcein but increased the oxidation of H2-DCF by approximately 50%. Similar changes were detected using electron spin resonance spectroscopy. Inhibition of the NADPH oxidase using gp91ds-tat prevented the Ang II-induced increase in DCF fluorescence, without affecting cells loaded with H2-calcein. Diphenylene iodonium (DPI), which inhibits all flavin-dependent enzymes, including those in the respiratory chain, had little effect on the basal but prevented the Ang II-induced oxidation of H2-DCF. In contrast, DPI inhibited H2-calcein oxidation in non-stimulated cells by almost 50%. Blockade of respiratory chain complex I inhibited H2-calcein oxidation, whereas inhibitors of complex III were without effect. Calcein accumulated in the mitochondria, whereas DCF was localized in the cytoplasm. In submitochondrial particles, H2-calcein, but not H2-DCF inhibited complex I activity. These observations indicate that H2-DCF is an indicator for intracellular ROS, whereas the oxidation of H2-calcein most likely occurs as a consequence of direct electron transfer to mitochondrial complex I.
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PMID:Analysis of dichlorodihydrofluorescein and dihydrocalcein as probes for the detection of intracellular reactive oxygen species. 1576 50

Since radiation-induced caspase-dependent apoptosis and ROS generation were partially prevented by HSP25 overexpression, similar to the treatment of control cells with antioxidant agents such as DPI and tiron, questions arise whether radiation-mediated ROS generation contributes to the apoptotic cell death, and also whether HSP25 overexpression can reduce ROS mediated apoptotic cell death. In the present study, radiation-induced cytochrome c release from mitochondria and activation of caspases accompanied by a decrease of mitochondrial membrane potential in Jurkat T cells were shown to be inhibited by mitochondrial complex I inhibitor rotenone, suggesting that mitochondrial ROS might be important in radiation-induced caspase-dependent apoptosis. When HSP25 was overexpressed, effects similar to the treatment of cells with the antioxidants were obtained, indicating that HSP25 suppressed radiation-induced mitochondrial alteration that resulted in apoptosis. Furthermore, activation of p38 MAP kinase by radiation was associated with radiation-induced cell death and ROS production and PKCdelta was an upstream molecule for p38 MAP kinase activation, ROS generation and subsequent caspase-dependent apoptotic events. However, in the HSP25 overexpressed cells, the above-described effects were blocked. In fact, radiation-induced membrane translocation of PKCdelta and tyrosine phosphorylation were inhibited by HSP25. Based on the above data, we suggest that HSP25 downregulates PKCdelta, which is a key molecule for radiation-induced ROS generation and mitochondrial-mediated caspase-dependent apoptotic events.
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PMID:HSP25 inhibits radiation-induced apoptosis through reduction of PKCdelta-mediated ROS production. 1580 74


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