Cytosolic acidification and lysosomal alkalinization during TNF-α induced apoptosis in U937 cells

Nilsson, Cathrine; Johansson, Uno; Johansson, Ann-Charlotte; Kågedal, Katarina; Öllinger, Karin

doi:10.1007/s10495-006-7108-5

Cited by 83 publications

(69 citation statements)

References 42 publications

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“…1C). These results are consistent with those of Brunk and colleagues, who proposed that oxidative stress stimulates apoptosis via destabilization of lysosomes through the Fenton reaction [47], and results in cytosolic acidification via proton release [43]. Metabolic inhibition of the vacuolar ATPase or protonophore activity would also be expected to dissipate cellular proton gradients, accelerate the leakage of H + from acidic organelles, and result in net cytosolic acidification.…”

Section: Oxidative and Metabolic Stresses Induce Cytosolic Acidificationsupporting

confidence: 90%

“…Mechanisms proposed for cytosolic acidification include: dysregulation of ion transport [42]; proton leakage from acidic organelles [43]; and hydrolysis of high energy nucleotides [44]. Notably, the PD toxin 1-methyl-4-phenylpyridinium (MPP + ) impairs cellular energy metabolism and leads to a decrease in pHi [45].…”

Section: Oxidative and Metabolic Stresses Induce Cytosolic Acidificationmentioning

confidence: 99%

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Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Cole

DiEuliis

Leo

et al. 2008

Experimental Cell Research

176

163

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Mitochondrial dysfunction plays a central role in the selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) and is influenced by both environmental and genetic factors. Expression of the PD protein α-synuclein or its familial mutants often sensitizes neurons to oxidative stress and to damage by mitochondrial toxins. This effect is thought to be indirect, since little evidence physically linking α-synuclein to mitochondria has been reported. Here, we show that the distribution of α-synuclein within neuronal and non-neuronal cells is dependent on intracellular pH. Cytosolic acidification induces translocation of α-synuclein from the cytosol onto the surface of mitochondria. Translocation occurs rapidly under artificially-induced low pH conditions and as a result of pH changes during oxidative or metabolic stress. Binding is likely facilitated by low pH-induced exposure of the mitochondria-specific lipid cardiolipin. These results imply a direct role for α-synuclein in mitochondrial physiology, especially under pathological conditions, and in principle, link α-synuclein to other PD genes in regulating mitochondrial homeostasis.

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Section: Oxidative and Metabolic Stresses Induce Cytosolic Acidificationsupporting

confidence: 90%

Section: Oxidative and Metabolic Stresses Induce Cytosolic Acidificationmentioning

confidence: 99%

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Cole

DiEuliis

Leo

et al. 2008

Experimental Cell Research

176

163

View full text Add to dashboard Cite

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“…Afterward this detergent has been found to induce lysosomal rupture and apoptosis in several different types of cell models [14,15]. It remains unknown whether oxidative stress driven by lysosomal iron is involved in MSDH induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages

et al. 2011

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Edited by Vladimir SkulachevKeywords: Apoptosis Ferritin Lysosomes MnSOD GSH Oxidative stress a b s t r a c t Moderate lysosomal membrane permeabilization (LMP) is an important inducer of apoptosis. Macrophages are professional scavengers and are rich in hydrolytic enzymes and iron. In the present study, we found that LMP by lysosomotropic detergent MSDH resulted in early up-regulation of lysosomal cathepsins, oxidative stress and ferritin up-regulation, and cell death. Lysosomotropic base NH 4 Cl reduced the ferritin induction and oxidative stress in apoptotic cells induced by MSDH. Cysteine cathepsin inhibitors significantly protected cell death and oxidative stress, but had less effect on ferritin induction. We conclude that oxidative stress induced by lysosomal rupture causes ferritin induction with concomitant mitochondrial damage, which are the potential target for prevention of cellular oxidative stress and cell death induced by typical lysosomotropic substances in different disorders.

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“…Several apoptosis-stimulating events, such as formation of the apoptosome, activation of caspases (49,50), or stimulation of leukocyte elastase inhibitor/leukocyte-derived DNase II (51), are enhanced by decreasing cytosolic pH. Recently, it has been shown that treatment of U937 cells with TNF resulted in lysosomal membrane permeabilization that was associated with an increased release of cathepsin D and cytosol acidification (8). In addition, treatment of cancer cells with inhibitors of the vacuolar-type H ϩ -ATPase (V-ATPase) have been shown to induce alkalinization of lysosomal pH, cytosol acidification, lysosomal membrane permeabilization, and caspase activation (52).…”

Section: Discussionmentioning

confidence: 99%

Lysosomal Serine Protease CLN2 Regulates Tumor Necrosis Factor-α-mediated Apoptosis in a Bid-dependent Manner

Autefage

Albinet

Garcia

et al. 2009

Journal of Biological Chemistry

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Apoptosis is a highly organized, energy-dependent program by which multicellular organisms eliminate damaged, superfluous, and potentially harmful cells. Although caspases are the most prominent group of proteases involved in the apoptotic process, the role of lysosomes has only recently been unmasked. This study investigated the role of the lysosomal serine protease CLN2 in apoptosis. We report that cells isolated from patients affected with late infantile neuronal ceroid lipofuscinosis (LINCL) having a deficient activity of CLN2 are resistant to the toxic effect of death ligands such as tumor necrosis factor (TNF), CD95 ligand, or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not to receptor-independent stress agents. CLN2-deficient cells exhibited a defect in TNF-induced Bid cleavage, release of cytochrome c, and caspase-9 and -3 activation. Moreover, extracts from CLN2-overexpressing cells or a CLN2 recombinant protein were able to catalyze the in vitro cleavage of Bid. Noteworthy, correction of the lysosomal enzyme defect of LINCL fibroblasts using a medium enriched in CLN2 protein enabled restoration of TNF-induced Bid and caspase-3 processing and toxicity. Conversely, transfection of CLN2-corrected cells with small interfering RNA targeting Bid abrogated TNF-induced cell death. Altogether, our study demonstrates that genetic deletion of the lysosomal serine protease CLN2 and the subsequent loss of its catalytic function confer resistance to TNF in non-neuronal somatic cells, indicating that CLN2 plays a yet unsuspected role in TNF-induced cell death.

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Cytosolic acidification and lysosomal alkalinization during TNF-α induced apoptosis in U937 cells

Cited by 83 publications

References 42 publications

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages

Lysosomal Serine Protease CLN2 Regulates Tumor Necrosis Factor-α-mediated Apoptosis in a Bid-dependent Manner

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