RETRACTED ARTICLE: Glucose-6-phosphate dehydrogenase plays a crucial role in protection from redox-stress-induced apoptosis

Fico, Annalisa; Paglialunga, F; Cigliano, Luisa; Abrescia, Paolo; Verde, Pasquale; Martini, Giuseppe; Iaccarino, Ingram; Filosa, Stefania

doi:10.1038/sj.cdd.4401420

Cited by 129 publications

(99 citation statements)

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“…Potential antiapoptotic effects of metabolic channeling through the pentose phosphate pathway Several reports have suggested antiapoptotic roles for the PPP (Tian et al, 1999;Fico et al, 2004). As the principal cellular source of the reduced forms of both nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), PPP flux plays a major role in cellular redox homeostasis and suggests a non-exclusive alternate mechanism whereby glucose metabolism can contribute to cell survival (Figure 4).…”

Section: How Do Growth Factors and Akt Mediate Hexokinase-mitochondrimentioning

confidence: 99%

Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

2006

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Cell survival has been closely linked to both trophic growth factor signaling and cellular metabolism. Such couplings have obvious physiologic and pathophysiologic implications, but their underlying molecular bases remain incompletely defined. As a common mediator of both the metabolic and anti-apoptotic effects of growth factors, the serine/threonine kinase Akt -also known as protein kinase B or PKB -is capable of regulating and coordinating these inter-related processes. The glucose dependence of the antiapoptotic effects of growth factors and Akt plus a strong correlation between Akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. Mitochondrial hexokinases catalyse the first obligatory step of glucose metabolism and directly couple extramitochondrial glycolysis to intramitochondrial oxidative phosphorylation, and are thus well suited to play this role. The ability of Akt to regulate energy metabolism appears to have evolutionarily preceded the capacity to control cell survival. This suggests that Akt-dependent metabolic regulatory functions may have given rise to glucose-dependent antiapoptotic effects that evolved as an adaptive sensing system involving hexokinases and serve to ensure mitochondrial homeostasis, thereby coupling metabolism to cell survival. We hypothesize that the enlistment of Akt and hexokinase in the control of mammalian cell apoptosis evolved as a response to the recruitment of mitochondria to the apoptotic cascade. The central importance of mitochondrial hexokinases in cell survival also suggests that they may represent viable therapeutic targets in cancer.

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Section: How Do Growth Factors and Akt Mediate Hexokinase-mitochondrimentioning

confidence: 99%

Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

2006

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“…74 Impairment of G6PD sensitizes cells to oxidant-induced apoptosis. 75 GSH depletion during apoptosis is also paralleled by decreases in NADPH availability, which might contribute to a sustained cellular redox imbalance by impairing GSSG reduction by GR. 76 Increased NADPH formation through the penthose pathway has been shown to protect against apoptosis induced by excitotoxicity, death receptors, and serum deprivation.…”

Section: Figure 1 Apoptotic Signaling Pathways (See Text For Further mentioning

confidence: 99%

Apoptosis and glutathione: beyond an antioxidant

2009

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Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms. Apoptosis or programmed cell death is a ubiquitous homeostatic process involved in numerous biological systems. Under physiological conditions it is critical not only in the turnover of cells in tissues but also during normal development and senescence. Moreover, its deregulation has been widely observed to occur as either a cause or consequence of distinct pathologies including cancer, autoimmune, and neurodegenerative diseases. Apoptosis is a highly organized program induced by a myriad of stimuli that are characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations in individual cells without involving an inflammatory response. Early stages of apoptosis are characterized by initiator caspase activation, cell shrinkage, loss of plasma membrane lipid asymmetry, and chromatin condensation. The execution phase of apoptosis is characterized by activation of executioner caspases and endonucleases, apoptotic body formation, and cell fragmentation 1 (Figure 1). Interestingly, recent studies have shown that changes in the intracellular milieu of the cells, such as alterations in the redox environment, are important regulators of the progression to apoptosis. 2 These discoveries have lead to the concept of a permissive apoptotic environment necessary for the activation of the proper signaling pathways regulating apoptosis. Glutathione (GSH) depletion is an early hallmark in the progression of cell death in response to a variety of apoptotic stimuli in numerous cell types 3,4 (Figure 2), although the exact role of GSH depletion in apoptosis is still controversial. We review recent data that show new insights into the understanding of the causes and consequences that alterations in the redox environment of the cell have on apoptosis.The Role of GSH in the Regulation of Apoptosis GSH synthesis, depletion, and apopt...

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“…Therein, the authors also referred to our studies described in Cell Death and Differentiation. 2 Efferth et al…”

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“…In our paper, 2 we investigated in wild-type and G6pd-deleted (G6pdD) mouse embryonic stem (ES) cells the signalling events activating an apoptotic pathway downstream GSH oxidation. These authors objected against the statement 'for the first time a role for G6PD in the protection from redoximbalance-induced apoptosis and necrosis has been clearly assigned', 2 claming that such a finding was reported in their 1995 paper. 3 In our opinion, the two studies are not comparable.…”

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RETRACTED ARTICLE: Glucose-6-phosphate dehydrogenase plays a crucial role in protection from redox-stress-induced apoptosis

Cited by 129 publications

References 35 publications

Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

Apoptosis and glutathione: beyond an antioxidant

Reply to ‘Role of glucose-6-phosphate dehydrogenase for oxidative stress and apoptosis’

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