Novel roles for glutathione in gene expression, cell death, and membrane transport of organic solutes

Hammond, Christine L.; Lee, Thomas K.; Ballatori, Nazzareno

doi:10.1016/s0168-8278(01)00037-x

Cited by 188 publications

(128 citation statements)

References 101 publications

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“…Moreover, because GSH is negatively charged under physiological conditions, there is also an electrical gradient that favors GSH efflux from cells. 28 Increasing extracellular GSH level, however, may counteract this tendency and decrease the driving force of GSH extrusion.…”

Section: Discussionmentioning

confidence: 99%

Impairment of Na+,K+-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide

Yin

Cheng

Shen³

et al. 2007

Leukemia

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Section: Discussionmentioning

confidence: 99%

Impairment of Na+,K+-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide

Yin

Cheng

Shen³

et al. 2007

Leukemia

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“…GSH is required for the maintenance of the thiol redox status of the cell, protection against oxidative damage, detoxification of reactive metals and electrophiles, storage and transport of cysteine, DNA synthesis, cell cycle regulation and cell differentiation (47). The key functional element of glutathione is the cysteinyl moiety, which provides the reactive thiol group.…”

Section: Glutathione Peroxidase and Other Glutathione Related Systemsmentioning

confidence: 99%

Mitochondrial dysfunction in human pathologies

Monsalve¹

2007

Front Biosci

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The integrity of mitochondrial function is fundamental to cell life. The cell demands for mitochondria and their complex integration into cell biology, extends far beyond the provision of ATP. It follows that disturbances of mitochondrial function lead to disruption of cell function, expressed as disease or even death. Mitochondria are major producers of free radical species and also possibly of nitric oxide, and are, at the same time, major targets for oxidative damage. In this review we consider recent developments in our knowledge of how the mitochondrial production of reactive oxygen species (ROS) plays a critical role in several major human pathologies. We will also consider recent advances in our understanding of the molecular mechanisms involved in mitochondrial ROS detoxification.

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“…Apoptosis has been widely reported to be modulated by changes in the redox status of the cell; however, the precise mechanisms involved are still unclear (6,7). Reduced glutathione (GSH) is the most abundant low molecular weight thiol in animal cells and is involved in many cellular processes including antioxidant defense, drug detoxification, cell signaling, and cell proliferation (8,9). In addition, alterations in its concentration have been demonstrated as a common feature of many pathological situations including AIDS, neurodegenerative diseases, and cancer (9,10).…”

mentioning

confidence: 99%

Glutathione Depletion Is Necessary for Apoptosis in Lymphoid Cells Independent of Reactive Oxygen Species Formation

Franco

Panayiotidis²,

Cidlowski

2007

Journal of Biological Chemistry

242

193

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Changes in the intracellular redox environment of cells have been reported to be critical for the activation of apoptotic enzymes and the progression of programmed cell death. Glutathione (GSH) depletion is an early hallmark observed in apoptosis, and we have demonstrated that GSH efflux during death receptor-mediated apoptosis occurs via a GSH transporter. We now evaluate the relationship between GSH depletion, the generation of reactive oxygen species (ROS), and the progression of apoptosis. Simultaneous single cell analysis of changes in GSH content and ROS formation by multiparametric FACS revealed that loss of intracellular GSH was paralleled by the generation of different ROS including hydrogen peroxide, superoxide anion, hydroxyl radical, and lipid peroxides. However, inhibition of ROS formation by a variety of antioxidants showed that GSH loss was independent from the generation of ROS. Furthermore, GSH depletion was observed to be necessary for ROS generation. Interestingly, high extracellular thiol concentration (GSH and N-acetyl-cysteine) inhibited apoptosis, whereas, inhibition of ROS generation by other non-thiol antioxidants was ineffective in preventing cell death. Finally, GSH depletion was shown to be a necessary for the progression of apoptosis activated by both extrinsic and intrinsic signaling pathways. These results document a necessary and critical role for GSH loss in apoptosis and clearly uncouple for the first time GSH depletion from ROS formation.Apoptosis or programmed cell death is a ubiquitous, evolutionary conserved process. Under physiological conditions it is important not only in the turnover of cells in all tissues, but also during the normal development and senescence of the organism. Moreover, its deregulation has been observed to occur as either a cause or consequence of distinct pathologies (1, 2). For example, apoptosis mediated by Fas ligand (FasL) 3 receptor (Fas/CD95/Apo-1) activation is necessary for the immune system homeostasis because of its role in the rapid clearance of immunoreactive T cells maintaining the immune balance and reducing the risk of autoimmune diseases (3). Apoptosis is a highly organized process characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations. Initial stages of apoptosis are characterized by reactive oxygen species (ROS) formation, changes in intracellular ionic homeostasis, cell shrinkage, loss of membrane lipid asymmetry, and chromatin condensation. Later stages associated with the execution phase of apoptosis are characterized by activation of execution caspases and endonucleases, apoptotic body formation, and cell fragmentation (1, 4, 5). Apoptosis has been widely reported to be modulated by changes in the redox status of the cell; however, the precise mechanisms involved are still unclear (6, 7). Reduced glutathione (GSH) is the most abundant low molecular weight thiol in animal cells and is involved in many cellular processes including antioxidant defense, drug det...

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Novel roles for glutathione in gene expression, cell death, and membrane transport of organic solutes

Cited by 188 publications

References 101 publications

Impairment of Na+,K+-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide

Impairment of Na+,K+-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide

Mitochondrial dysfunction in human pathologies

Glutathione Depletion Is Necessary for Apoptosis in Lymphoid Cells Independent of Reactive Oxygen Species Formation

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