Glutathione Levels and Sensitivity to Apoptosis Are Regulated by Changes in Transaldolase Expression

Bánki, Katalin; Hutter, Eliza; Colombo, Emanuela; Gonchoroff, Nick J.; Perl, András

doi:10.1074/jbc.271.51.32994

Cited by 179 publications

(181 citation statements)

References 40 publications

(34 reference statements)

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“…Thus, low GSH content might also inhibit CD3-induced H 2 O 2 production. Nevertheless, GSH deficiency predisposes for ROI-induced cell death [4,34]. Diminished H 2 O 2 -induced apoptosis of cells with low baseline GSH levels indicates a severe dysfunction of redox signaling in patients with SLE [10].…”

Section: Mhp Increased Roi Production Cytoplasmic Alkalinization Anmentioning

confidence: 99%

“…Elevated NO production might also contribute to increased spontaneous apoptosis [41]. Increased ROI levels confer sensitivity to H 2 O 2 , NO, TNF-α or Fas-induced cell death [34]. Therefore, persistent MHP, causing increased ROI production (a trigger of apoptosis) and depletion of ATP (required for AICD), might be responsible for the paradox of increased spontaneous apoptosis and diminished AICD in SLE.…”

Section: Mhp Increased Roi Production Cytoplasmic Alkalinization Anmentioning

confidence: 99%

“…Regeneration of GSH by glutathione reductase from its oxidized form, GSSG, depends on NADPH produced by the pentose phosphate pathway (PPP) [43]. ROI levels and ΔΨ m are regulated by transaldolase through the supply of reducing equivalents from PPP [3,34], Ca 2+ fluxing and NO production [23]. Whereas ROIs have been considered as toxic byproducts of aerobic existence, evidence is now accumulating that controlled levels of ROIs modulate various aspects of cellular function and are necessary for signal transduction pathways, including those mediating T-cell activation and apoptosis [1].…”

Section: Box 1 Regulation Of the Mitochondrial Transmembrane Potentimentioning

confidence: 99%

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Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Perl

Gergely

Nagy

et al. 2004

Trends in Immunology

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220

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T-cell activation, proliferation and selection of the cell death pathway depend on the production of reactive oxygen intermediates (ROIs) and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ). Mitochondrial hyperpolarization (MHP) and ATP depletion represent early and reversible steps in T-cell activation and apoptosis. By contrast, T cells of patients with systemic lupus erythematosus (SLE) exhibit persistent MHP, cytoplasmic alkalinization, increased ROI production and depleted ATP, which mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Necrotic, but not apoptotic, cell lysates activate dendritic cells and might account for increased interferon a production and inflammation in lupus patients. MHP is proposed as a key mechanism of SLE pathogenesis and is therefore a target for pharmacological intervention.Innate and adaptive immune responses depend on controlled production of ATP and reactive oxygen intermediates (ROIs) in mitochondria. In response to antigenic stimulation, clonal expansion of T and B cells are continuously downsized and potentially autoreactive cells are eliminated by apoptosis. An array of signals through the T-cell receptor (TCR), costimulatory molecules, cell death receptors, lymphokines, and other circulating metabolites, such as ATP, NAD, cADPR, glucose, glutathione, nitric oxide (NO) and ROIs, determine the fate of T cells [1]. T-cell activation and death pathway selection depend on the production of ROIs and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ) (Box 1). Disruption of ΔΨ m has been proposed as the point of no return in apoptotic signaling [2] T-cell activation is regulated by mitochondrial ROI productionROIs modulate T-cell activation, cytokine production and proliferation at multiple levels [12]. The antigen-binding αβ or γδTCR is associated with a multimeric receptor module comprising the CD3γδε and TCRζ chains. The cytoplasmic domains of the CD3 and ζ chains contain a common motif, termed the immunoreceptor tyrosinebased activation motif (ITAM), which is crucial for the coupling of intracellular tyrosine kinases [13]. . Thus, expression of cytokines can be selectively regulated by oxidative stress depending on the relative expression level of transcription factors involved (e.g. IL-2 is expressed through a promoter that has AP-1 and NFAT motifs, and IL-4 is expressed through an AP-1-less NFAT enhancer; Figure 1). Redox control of apoptosis signal processingProgrammed cell death (PCD) or apoptosis is a physiological mechanism for elimination of autoreactive lymphocytes during development. Signaling through the Fas or structurally related TNF family of cell-surface death receptors has emerged as a major pathway in the elimination of unwanted cells under physiological and disease conditions [18]. Fas and TNF receptors mediate cell death through cytoplasmic death domains (DDs) shared by both receptors [19]. They ...

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Section: Mhp Increased Roi Production Cytoplasmic Alkalinization Anmentioning

confidence: 99%

Section: Mhp Increased Roi Production Cytoplasmic Alkalinization Anmentioning

confidence: 99%

Section: Box 1 Regulation Of the Mitochondrial Transmembrane Potentimentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Perl

Gergely

Nagy

et al. 2004

Trends in Immunology

Self Cite

220

142

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“…Elevation of Δψ m or mitochondrial hyperpolarization (MHP) was discovered in our laboratory [6]. MHP in T cells is facilitated by depletion of GSH and NADPH triggered by over-expression of the PPP enzyme transaldolase (TAL) [6,7]. Transient MHP is an early event preceding caspase activation, phosphatidylserine (PS) externalization, and disruption of Δψ m in Fas- [6] and H 2 O 2 -induced apoptosis of Jurkat human leukemia T cells and normal human peripheral blood lymphocytes (PBL) [8].…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

Nagy

Koncz

Fernández

et al. 2007

Free Radical Biology and Medicine

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T lymphocyte activation is associated with nitric oxide (NO) production that plays an essential role in multiple T cell functions. NO acts as a messenger, activating soluble guanyl cyclase and participating in the transduction signaling pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial membrane potential and mitochondrial biogenesis in many cell types, including lymphocytes. Mitochondrial hyperpolarization (MHP), an early and reversible event during both T lymphocyte activation and apoptosis, is regulated by NO. Here, we discuss recent evidence that NO-induced MHP represents a molecular switch in multiple T cell signaling pathways. Overproduction of NO in systemic lupus erythematosus (SLE) induces mitochondrial biogenesis and alters Ca 2+ signaling. Thus, while NO plays a physiological role in lymphocyte cell signaling, its overproduction may disturb normal T cell function, contributing to the pathogenesis of autoimmunity.

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“…The oxidative phase is primarily dependent on G6PD (35). While the control of the nonoxidative branch is less well established, transaldolase (TAL) has been proposed as its rate-limiting enzyme (23,35,37).…”

Section: Role Of the Ppp In Redox Signaling And Maintenance Of The MImentioning

confidence: 99%

The pathogenesis of transaldolase deficiency

Perl¹

2007

IUBMB Life

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SummaryThe signaling networks that mediate cell growth, differentiation, and survival are dependent on complex metabolic and redox pathways. Metabolism of glucose through the pentose phosphate pathway (PPP) fulfills two unique functions: formation of ribose 5-phosphate for the synthesis of nucleotides, RNA, and DNA in support cell growth and formation of NADPH for biosynthetic reactions and neutralization of reactive oxygen intermediates (ROI). Balancing of NADPH and ROI levels by the PPP enzyme transaldolase (TAL) regulates the mitochondrial trans-membrane potential (Dw m ), a critical checkpoint of ATP synthesis and cell survival. While complete deficiency of glucose 6-phosphate dehydrogenase (G6PD) or transketolase (TK) is lethal, TAL-deficient mice developed normally with the exception of male sterility due to structural and functional damage of sperm cell mitochondria. Recently, two cases of complete TAL deficiency have been reported in patients with liver cirrhosis which results from increased cell death of hepatocytes. Delineation of the cell type-specific role that TAL plays in the PPP and cell death signal processing will be critical for understanding the pathogenesis of TAL deficiency.

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Glutathione Levels and Sensitivity to Apoptosis Are Regulated by Changes in Transaldolase Expression

Cited by 179 publications

References 40 publications

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

The pathogenesis of transaldolase deficiency

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