Mitochondrial glutathione oxidation correlates with age‐associated oxidative damage to mitochondrial DNA

Asunción, José García de la; Millán, A; Plá, Rosa Corcoy i; Bruseghini, L; Esteras, Antonio; Pallardó, Federico V.; Sastre, Juan; Viña, José

doi:10.1096/fasebj.10.2.8641567

Cited by 274 publications

(119 citation statements)

References 8 publications

(12 reference statements)

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“…Although there is presently no validated, single measure or a quantitative scale for expressing the absolute or an overall level of "oxidative stress" in tissues, the glutathione redox state, represented by the GSH:GSSG ratio, is widely used as a surrogate for determining the direction of the shift in the level of oxidative stress in tissues (de la Asuncion et al, 1996;Schafer and Buettner, 2001;Dröge 2002). Enhanced in vivo fluxes of ROS are known to cause oxidation of GSH into GSSG by direct interaction with ROS or by being a substrate for the enzymatic elimination of peroxides, among others (reviewed in Schafer and Buettner, 2001;Reed 1990;Dickinson and Forman, 2002).…”

Section: Discussionmentioning

confidence: 99%

Comparison between the effects of aging and hyperoxia on glutathione redox state and protein mixed disulfides in Drosophila melanogaster

Rebrin

Sohal

2006

Mechanisms of Ageing and Development

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The main purpose of this study was to determine whether experimental enhancement of oxidative stress by exposure to hyperoxia is an appropriate model for the acceleration of the normal aging process or for establishing a causal association between oxidative stress and aging. Insect tissues are directly exposed to ambient air via the tracheolar invaginations and are thus highly susceptible to oxidative stress under hyperoxic conditions. Amounts of glutathione (GSH), glutathione disulfide (GSSG) and protein mixed disulfides (PrSSG) were compared under normoxic and 100% ambient oxygen in males of two different strains of Drosophila melanogaster (Oregon R (WT) and y w strains). The reason for using two different strains was to preclude the effects of genetic background and to determine whether variations in longevity of the two strains are associated with resistance to oxidative stress. Amounts of GSSG and PrSSG increased whereas GSH:GSSG ratios declined as a function of age in both strains. Under hyperoxia, y w flies did not exhibit an increase in GSSG amount or a decline in GSH:GSSG ratio, whereas WT flies showed a decline in GSH:GSSG ratio only during the later part of hyperoxic exposure. In neither strain there was a progressive increase in PrSSG amount under hyperoxia. Results indicate that hyperoxia (100% oxygen) neither reproduces nor accelerates the pattern of alterations in glutathione redox state and PrSSG content observed during aging under normoxic conditions, although some other indicators of oxidative stress may be affected.

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Section: Discussionmentioning

confidence: 99%

Comparison between the effects of aging and hyperoxia on glutathione redox state and protein mixed disulfides in Drosophila melanogaster

Rebrin

Sohal

2006

Mechanisms of Ageing and Development

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“…Telomerase is regulated by changes in glutathione redox potential at values that are similar to those in vivo (20,21) (see Fig. 2), and changes in telomerase are modulated in coordination with changes in critical cell cycle proteins, particularly Id2 and E2F4.…”

Section: Modulation Of Glutathione Levels Affects the Rate Of Cell Grmentioning

confidence: 97%

Glutathione Regulates Telomerase Activity in 3T3 Fibroblasts

Borrás¹,

Esteve²,

Viña

et al. 2004

Journal of Biological Chemistry

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Changes in telomerase activity have been associated either with cancer, when activity is increased, or with cell cycle arrest when it is decreased. We report that glutathione, a physiological antioxidant present at high intracellular concentrations, regulates telomerase activity in cells in culture. Telomerase activity increases in 3T3 fibroblasts before exponential cell growth. The peak of telomerase activity takes place 24 h after plating and coincides with the maximum levels of glutathione in the cells. When cells are treated with buthionine sulfoximine, which decreases glutathione levels in cells, telomerase activity decreases by 60%, and cell growth is delayed. Glutathione depletion inhibits expression of E2F4 and Id2, which regulate the cell cycle. When glutathione levels are restored after incubation with glutathione monoethylester, telomerase activity and the cell cyclerelated proteins return to control values. To discover the effect of glutathione redox status on the telomerase multicomplex structure, we incubated protein extracts from fibroblasts with different glutathione redox buffers. Telomerase activity is maximal under reduced conditions i.e. when the reduced/oxidized glutathione ratio is high. Consequently glutathione concentration parallels telomerase activity. These results underscore the main role of glutathione in the control of telomerase activity and of the cell cycle.The eukaryotic chromosomes are capped by telomeres, which consist of telomeric DNA repeated in tandem, associated with several proteins. These structures play an important role in the stability and the complete replication of the chromosomes. Conventional DNA polymerases cannot fully replicate the 3Ј-end of the lagging strand of linear molecules, and therefore in every cell division telomeric sequences are lost (1).Telomerase is an important enzyme that ensures the maintenance of normal telomere length. This activity is high in human cancers (2) but virtually absent in normal tissues, except germinal cells (3). Telomerase regulation is not well understood, but its changes are related to both cancer and aging (4).Glutathione (GSH) 1 is the most abundant non-protein thiol in cells. Its activity ranges in the level of 5 mol/gram of tissue (5), i.e. higher than that of glucose. It has a critical role in the maintenance thiol redox status in cells. Changes in the redox ratio (GSH/GSSG) of GSH are relevant to the maintenance of enzyme activities (6). The aim of this work was to study the role of glutathione in the regulation of the telomerase activity in cells. We found that cellular glutathione levels correlate with telomerase activity in 3T3 fibroblasts. The peak of telomerase activity coincides with the GSH peak. Depletion of GSH with buthionine sulfoximine (BSO) reduces the telomerase activity and that of regulators of the cell cycle such as Id2 and E2F4 after 24 and 48 h of treatment. Furthermore, changes in the GSH/GSSG redox potential modulate telomerase activity. We concluded that the GSH levels in cells and subsequently oxi...

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“…An enhanced ROS level in vivo causes oxidation of GSH into GSSG by direct interaction with ROS or by being a substrate for the enzymatic elimination of peroxides (28 -30). Therefore, a glutathione redox state, represented by the GSH:GSSG ratio, is widely used as a surrogate for determining the direction of the shift in the level of oxidative stress in tissues (28,31,32). Although it is not clear how flies with Dpt overexpression increase Gst gene expression and enzyme activities, our data led us to hypothesize that hyperoxia might not induce ROS accumulation or have less of an effect on redox homeostasis in these Dpt overexpression flies compared with controls.…”

Section: Overexpression Of Diptericin Increases Hyperoxia Tolerance-mentioning

confidence: 99%

Antimicrobial Peptides Increase Tolerance to Oxidant Stress in Drosophila melanogaster

Zhao¹,

Zhou²,

Haddad

2011

Journal of Biological Chemistry

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It is well appreciated that reactive oxygen species (ROS) are deleterious to mammals, including humans, especially when generated in abnormally large quantities from cellular metabolism. Whereas the mechanisms leading to the production of ROS are rather well delineated, the mechanisms underlying tissue susceptibility or tolerance to oxidant stress remain elusive. Through an experimental selection over many generations, we have previously generated Drosophila melanogaster flies that tolerate tremendous oxidant stress and have shown that the family of antimicrobial peptides (AMPs) is over-represented in these tolerant flies. Furthermore, we have also demonstrated that overexpression of even one AMP at a time (e.g. Diptericin) allows wild-type flies to survive much better in hyperoxia. In this study, we used a number of experimental approaches to investigate the potential mechanisms underlying hyperoxia tolerance in flies with AMP overexpression. We demonstrate that flies with Diptericin overexpression resist oxidative stress by increasing antioxidant enzyme activities and preventing an increase in ROS levels after hyperoxia. Depleting the GSH pool using buthionine sulfoximine limits fly survival, thus confirming that enhanced survival observed in these flies is related to improved redox homeostasis. We conclude that 1) AMPs play an important role in tolerance to oxidant stress, 2) overexpression of Diptericin changes the cellular redox balance between oxidant and antioxidant, and 3) this change in redox balance plays an important role in survival in hyperoxia.Oxygen is essential for aerobic life. However, except for the beneficial role in wound healing, too little or too much oxygen can induce morbidity and mortality (1, 2). Mammalian aging and numerous diseases such as neurodegenerative diseases and chronic inflammatory diseases, as well as injury to the heart, lungs, retina, brain, and other organs due to ischemia and reperfusion states, result, by and large, from oxidant injury (3-6). High O 2 -induced oxidant injury could occur in cells in every organ, especially in the lungs, retina, heart, and brain (7,8). Prolonged exposure to high O 2 generates excessive reactive oxygen species (ROS), 2 induces cell death and oxidative stress responses, affects the immune response and DNA integrity, and modulates cell growth (5, 9 -11).Drosophila melanogaster has similar O 2 response pathways as mammals, and research on flies has enhanced our understanding of oxidant stress (12)(13)(14). In the past, through an experimental selection design over many generations, we have successfully generated D. melanogaster flies that tolerate tremendously high O 2 -induced oxidative stress. Microarray analysis has revealed that the family of antimicrobial peptides (AMPs) is over-represented among the up-regulated genes in these tolerant flies. We have further demonstrated that overexpression of even one AMP gene at a time (e.g. Diptericin (Dpt)) allows wild-type flies to survive much better in hyperoxia (15). To our knowledge, this is t...

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Mitochondrial glutathione oxidation correlates with age‐associated oxidative damage to mitochondrial DNA

Cited by 274 publications

References 8 publications

Comparison between the effects of aging and hyperoxia on glutathione redox state and protein mixed disulfides in Drosophila melanogaster

Comparison between the effects of aging and hyperoxia on glutathione redox state and protein mixed disulfides in Drosophila melanogaster

Glutathione Regulates Telomerase Activity in 3T3 Fibroblasts

Antimicrobial Peptides Increase Tolerance to Oxidant Stress in Drosophila melanogaster

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