Glutamate-cysteine ligase attenuates TNF-induced mitochondrial injury and apoptosis

Botta, Dianne; Franklin, Christopher C.; White, Collin C.; Krejsa, Cecile M.; Dabrowski, Michael J.; Pierce, Robert H.; Fausto, Nelson; Kavanagh, Terrance J.

doi:10.1016/j.freeradbiomed.2004.05.027

Cited by 42 publications

(55 citation statements)

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“…GCLC represents the rate-limiting enzyme in GSH synthesis; it is composed of catalytic and modifier subunits, and transcriptional activation of cognate genes occurs through an antioxidant response element that plays an essential role in regulating the cellular responses to oxidative stress (44). In this study, CLA's ability to elicit cytoprotective effects (enhanced cellular GSH and GCLS expression) at lower doses was shown for the first time, and this is in agreement with literature data showing the antiapoptotic effect of GCLC (45). In addition, our in vivo results showing CLA-induced upregulation of GSH via the enhanced expression of GCLC in vivo are consistent with recent findings showing the ability of other PPARg ligands to upregulate the expression of stress-responding enzymes and/or to enhance cellular redox status (23,46,47).…”

Section: Discussionsupporting

confidence: 91%

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice

Bergamo

Luongo

Maurano

et al. 2006

Journal of Lipid Research

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Conjugated linoleic acid (CLA), a naturally occurring peroxisome proliferator-activated receptor g (PPARg) ligand, exhibits proapoptotic, immunomodulatory, and anticancer properties. In this study, we examined the biological effects of CLA administration in the MRL/MpJ-Fas lpr mouse, an animal model of systemic lupus erythematosus (SLE). We found that CLA exerted apparently opposed activities in in vitro experiments, depending on its concentration: 100 mM CLA downregulated IFNg synthesis and cell proliferation of splenocytes, in association with apoptosis induction and a decrease of intracellular thiols (GSH 1 GSSG), whereas 25 mM CLA did not significantly influence cell proliferation but enhanced the expression of g-glutamylcysteine ligase catalytic subunit (GCLC) and intracellular GSH concentration. Interestingly, the antiproliferative effect at 100 mM was not inhibited by the PPARg antagonist GW9662. In vivo, CLA administration drastically reduced SLE signs (splenomegaly, autoantibodies, and cytokine synthesis), a condition paralleled by the enhancement of GCLC expression and intracellular GSH content. Moreover, CLA administration significantly downregulated nuclear factor kB activity independent of PPARg activation and apoptosis induction. In conclusion, enhanced GSH content and GCLC expression in CLA-treated mice suggest a novel biochemical mechanism underlying its immunomodulatory activity and the beneficial effects on murine SLE signs.-Bergamo, P., D. Luongo, F. Maurano, G. Mazzarella, R. Stefanile, and M. Rossi. Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Fas lpr mice. J. Lipid Res.

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Section: Discussionsupporting

confidence: 91%

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice

Bergamo

Luongo

Maurano

et al. 2006

Journal of Lipid Research

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“…While it is still unclear how altered GSH homeostasis affects apoptotic cell death, GSH is thought to function at the level of the mitochondrion to prevent the loss of mitochondrial membrane potential and release of pro-apoptotic factors into the cytoplasm (Circu and Aw, 2008). Consistent with this working model, we have found that increased GCL activity resulting from GCL overexpression inhibits TNF-induced apoptosis by maintaining mitochondrial integrity and preventing the release of cytochrome c (Botta et al ., 2004). While TNF induces by cytochrome c release indirectly via Bid-mediated mitochondrial dysfunction, As3+ initiates cytochrome c release and activation of the apoptotic machinery by a direct effect on the mitochondrion (Larochette et al ., 1999; Costantini et al ., 2000).…”

Section: Introductionsupporting

confidence: 73%

Enhanced glutathione biosynthetic capacity promotes resistance to As3+-induced apoptosis

Thompson

Franklin

2010

Toxicology Letters

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Trivalent arsenite (As3+) is a known human carcinogen capable of inducing both cellular transformation and apoptotic cell death by mechanisms involving the production of reactive oxygen species. The tripeptide antioxidant glutathione (GSH) constitutes a vital cellular defense mechanism against oxidative stress. While intracellular levels of GSH are an important determinant of cellular susceptibility to undergo apoptotic cell death, it is not known whether cellular GSH biosynthetic capacity per se regulates As3+-induced apoptosis. The rate-limiting enzyme in GSH biosynthesis is glutamate cysteine ligase (GCL), a heterodimeric holoenzyme composed of a catalytic (GCLC) and a modifier (GCLM) subunit. To determine whether increased GSH biosynthetic capacity enhanced cellular resistance to As3+-induced apoptotic cell death, we utilized a mouse liver hepatoma (Hepa-1c1c7) cell line stably overexpressing both GCLC and GCLM. Overexpression of the GCL subunits increased GCL holoenzyme formation and activity and inhibited As3+-induced apoptosis. This cytoprotective effect was associated with a decrease in As3+-induced caspase activation, cleavage of caspase substrates and translocation of cytochrome c to the cytoplasm. In aggregate, these findings demonstrate that enhanced GSH biosynthetic capacity promotes resistance to As3+-induced apoptosis by preventing mitochondrial dysfunction and cytochrome c release and highlight the role of the GSH antioxidant defense system in dictating hepatocyte sensitivity to As3+-induced apoptotic cell death.

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“…GCL, the rate-limiting enzyme in GSH biosynthesis, exists as a heterodimer comprising a large catalytic (GCLC) and a small modifier (GCLM) subunits (Griffith and Mulcahy, 1999). Overexpression of both GCL subunits has been shown to elevate intracellular GSH levels and protect cells from apoptosis caused by exposure to SIN-1 (Mulcahy et al, 1995;Manna et al, 1999;Botta et al, 2004). Exposure of rat aortic vascular smooth muscle cells to moderate doses of SNAP up to 24 h resulted in a significant increase in total GSH levels under conditions where no cytotoxicity was detected (Moellering et al, 1998).…”

Section: Roles Of Gcl and Gshmentioning

confidence: 99%

Role of Nrf2-mediated heme oxygenase-1 upregulation in adaptive survival response to nitrosative stress

et al. 2009

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Nitrosative stress caused by reactive nitrogen species such as nitric oxide and peroxynitrite overproduced during inflammation leads to cell death and has been implicated in the pathogenesis of many human ailments. However, relatively mild nitrosative stress may fortify cellular defense capacities, rendering cells tolerant or adaptive to ongoing and subsequent cytotoxic challenges, a phenomenon known as 'preconditioning' or 'hormesis'. One of the key components of cellular stress response is heme oxygenase-1 (HO-1), the rate limiting enzyme in the process of degrading potentially toxic free heme into biliverdin, free iron and carbon monoxide. HO-1 is upregulated by a wide array of stimuli and has antioxidant, anti-inflammatory and other cytoprotective functions. This review is intended to provide readers with a welldocumented account of the research done in the area of cellular adaptive survival response against nitrosative stress with special focus on the role of HO-1 upregulation, especially through activation of the transcription factor, Nrf2.

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Glutamate-cysteine ligase attenuates TNF-induced mitochondrial injury and apoptosis

Cited by 42 publications

References 50 publications

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice

Enhanced glutathione biosynthetic capacity promotes resistance to As3+-induced apoptosis

Role of Nrf2-mediated heme oxygenase-1 upregulation in adaptive survival response to nitrosative stress

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