Oxidative activation of antioxidant defence

Winyard, Paul G.; Moody, Christopher J.; Jacob, Claus

doi:10.1016/j.tibs.2005.06.001

Cited by 228 publications

(157 citation statements)

References 74 publications

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“…In another study, it was suggested that mitochondrial function directly benefits from a nonfragmented mitochondrial phenotype because this facilitates sharing of intramitochondrial antioxidants, matrix solutes, and ROS-damaged mitochondrial constituents (38). When not appropriately counterbalanced by the cell's endogenous antioxidant systems (68), ROS can damage proteins like CI, lipids, and mitochondrial DNA, thereby further compromising mitochondrial function (12,13,18). Interestingly, fragmented mitochondria were also functionally impaired (44).…”

Section: Are Changes In Mitochondrial Morphology During CI Deficiencymentioning

confidence: 99%

Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology?

Koopman¹,

Verkaart²,

Visch³

et al. 2007

American Journal of Physiology-Cell Physiology

125

116

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function of NADH:ubiquinone oxidoreductase or complex I (CI), the first and largest complex of the mitochondrial oxidative phosphorylation system, has been implicated in a wide variety of human disorders. To demonstrate a quantitative relationship between CI amount and activity and mitochondrial shape and cellular reactive oxygen species (ROS) levels, we recently combined native electrophoresis and confocal and video microscopy of dermal fibroblasts of healthy control subjects and children with isolated CI deficiency. Individual mitochondria appeared fragmented and/or less branched in patient fibroblasts with a severely reduced CI amount and activity (class I), whereas patient cells in which these latter parameters were only moderately reduced displayed a normal mitochondrial morphology (class II). Moreover, cellular ROS levels were significantly more increased in class I compared with class II cells. We propose a mechanism in which a mutation-induced decrease in the cellular amount and activity of CI leads to enhanced ROS levels, which, in turn, induce mitochondrial fragmentation when not appropriately counterbalanced by the cell's antioxidant defense systems. complex I; reactive oxygen species; microscopy; fluorescence MITOCHONDRIAL FUNCTION AND COMPLEX I DEFICIENCY

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Section: Are Changes In Mitochondrial Morphology During CI Deficiencymentioning

confidence: 99%

Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology?

Koopman¹,

Verkaart²,

Visch³

et al. 2007

American Journal of Physiology-Cell Physiology

125

116

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“…This is an important observation as, if these experiments had been carried out only in cells which had been cultured, long term, under hyperoxia (without inclusion of the long-term culture of cells at other O 2 concentrations), we would have concluded that the thioredoxin antioxidant system was not a valid target for increasing photodynamic cell killing. By targeting enzymes that comprise the thioredoxin antioxidant system, we have been able to demonstrate that this important pathway [74] is, in part, responsible for the resistance to oxidative stress-induced damage and cell death observed in cells cultured under hyperoxia. Cells cultured under hyperoxia also had a lower ratio of GSH:GSSG (Fig.…”

Section: Discussionmentioning

confidence: 99%

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Ferguson

Smerdon

Harries

et al. 2018

Free Radical Biology and Medicine

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In vivo, mammalian cells reside in an environment of 0.5-10% O 2 (depending on the tissue location within the body), whilst standard in vitro cell culture is carried out under room air. Little is known about the effects of this hyperoxic environment on treatment-induced oxidative stress, relative to a physiological oxygen environment. In the present study we investigated the effects of long-term culture under hyperoxia (air) on photodynamic treatment. Upon photodynamic irradiation, cells which had been cultured long-term under hyperoxia generated higher concentrations of mitochondrial reactive oxygen species, compared with cells in a physioxic (2% O 2 ) environment. However, there was no significant difference in viability between hyperoxic and physioxic cells. The expression of genes encoding key redox homeostasis proteins and the activity of key antioxidant enzymes was significantly higher after the long-term culture of hyperoxic cells compared with physioxic cells. The induction of antioxidant genes and increased antioxidant enzyme activity appear to contribute to the development of a phenotype that is resistant to oxidative stress-induced cellular damage and death when using standard cell culture conditions. The results from experiments using selective inhibitors suggested that the thioredoxin antioxidant system contributes to this phenotype. To avoid artefactual results, in vitro cellular responses should be studied in mammalian cells that have been cultured under physioxia. This investigation provides new insights into the effects of physioxic cell culture on a model of a clinically relevant photodynamic treatment and the associated cellular pathways.

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“…Trx peroxidases in addition to Trxs are the other components of the Trx system; the GSH system involves GSH peroxidase (Gpx) and glutaredoxin (Grx), an oxidoreductase acting on S-glutathionylated substrates (7,8). TRs and GRs are homodimeric NADPH-dependent flavoproteins that are structurally highly similar.…”

mentioning

confidence: 99%

Mapping the Catalytic Cycle of Schistosoma mansoni Thioredoxin Glutathione Reductase by X-ray Crystallography

Angelucci¹,

Dimastrogiovanni²,

Boumis

et al. 2010

Journal of Biological Chemistry

115

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Schistosomiasis is the second most widespread human parasitic disease. It is principally treated with one drug, praziquantel, that is administered to 100 million people each year; less sensitive strains of schistosomes are emerging. One of the most appealing drug targets against schistosomiasis is thioredoxin glutathione reductase (TGR). This natural chimeric enzyme is a peculiar fusion of a glutaredoxin domain with a thioredoxin selenocysteine (U)-containing reductase domain. Selenocysteine is located on a flexible C-terminal arm that is usually disordered in the available structures of the protein and is essential for the full catalytic activity of TGR. In this study, we dissect the catalytic cycle of Schistosoma mansoni TGR by structural and functional analysis of the U597C mutant. The crystallographic data presented herein include the following: the oxidized form (at 1.9 Å resolution); the NADPH-and GSH-bound forms (2.3 and 1.9 Å , respectively); and a different crystal form of the (partially) reduced enzyme (3.1 Å ), showing the physiological dimer and the entire C terminus of one subunit. Whenever possible, we determined the rate constants for the interconversion between the different oxidation states of TGR by kinetic methods. By combining the crystallographic analysis with computer modeling, we were able to throw further light on the mechanism of action of S. mansoni TGR. In particular, we hereby propose the putative functionally relevant conformational change of the C terminus after the transfer of reducing equivalents from NADPH to the redox sites of the enzyme.

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Oxidative activation of antioxidant defence

Cited by 228 publications

References 74 publications

Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology?

Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology?

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Mapping the Catalytic Cycle of Schistosoma mansoni Thioredoxin Glutathione Reductase by X-ray Crystallography

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