Sphingosine mediates TNFα-induced lysosomal membrane permeabilization and ensuing programmed cell death in hepatoma cells

Ullio, Chiara; Casas, Josefina; Brunk, Ulf T.; Sala, Giuseppina La; Fabriàs, Gemma; Ghidoni, Riccardo; Bonelli, Gabriella; Baccino, Francesco M.; Autelli, Riccardo

doi:10.1194/jlr.m022384

Cited by 70 publications

(45 citation statements)

References 45 publications

(56 reference statements)

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“…Importantly, a well-characterized pro-survival effect of the HSR, in particular HSP70, is toward oxidative stresses, ranging from cellular studies of protection against ROS and membrane oxidation to clinical studies of the effects of HSP70 on ischemia-reperfusion injury ( 12,13,(79)(80)(81) Not only heavy metals, but also a variety of lipids such as free fatty acids, arachidonic acid, SM, and sphingosine, have been shown to be directly involved in loss of lysosomal integrity; whereas cholesterol seems to serve a more protective role, which is in accordance with its proposed membrane-stabilizing effect ( 57,(82)(83)(84)(85)(86). Also, generation of ceramide alters the biophysical properties of cellular membranes ( 87 ).…”

Section: +mentioning

confidence: 73%

Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Ingemann

Kirkegaard

2014

Journal of Lipid Research

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The lysosomal storage diseases (LSDs) describe a heterogenous family of rare inherited diseases caused by mutations in lysosomal proteins and are characterized by accumulation of macromolecules or monomeric compounds inside organelles of the endo-lysosomal system ( 1-3 ). The LSDs present complex disease phenotypes with the mechanisms leading to pathology being poorly understood, as the disease and extent of pathology seem to depend on the spatiotemporal accumulation of substrates which have a variety of downstream effects depending on their cellular and physiological context ( Table 1 ). It is thus diffi cult to generalize for the LSDs, but as the origin of the diseases in all cases is a genetic lesion, which most often causes a misfolded dysfunctional protein, the cellular processes and responses related to misfolded proteins have to be considered as an integral part of the etiology of any of the diseases. Thus, the shared mechanistic principle of disturbed protein homeostasis and the fact that many LSDs also show an overlap of potentially toxic storage compounds might explain why the LSDs, despite their various monogenetic origins, share a number of cellular and clinical manifestations including perturbed lysosomal traffi cking and autophagy, increased oxidative stress, impaired calcium homeostasis, loss of lysosomal stability, increased Abstract Lysosomes play a vital role in the maintenance of cellular homeostasis through the recycling of cell constituents, a key metabolic function which is highly dependent on the correct function of the lysosomal hydrolases and membrane proteins, as well as correct membrane lipid stoichiometry and composition. The critical role of lysosomal functionality is evident from the severity of the diseases in which the primary lesion is a genetically defi ned loss-of-function of lysosomal hydrolases or membrane proteins. This group of diseases, known as lysosomal storage diseases (LSDs), number more than 50 and are associated with severe neurodegeneration, systemic disease, and early death, with only a handful of the diseases having a therapeutic option. Another key homeostatic system is the metabolic stress response or heat shock response (HSR), which is induced in response to a number of physiological and pathological stresses, such as protein misfolding and aggregation, endoplasmic reticulum stress, oxidative stress, nutrient deprivation, elevated temperature, viral infections, and various acute traumas. Importantly, the HSR and its cardinal members of the heat shock protein 70 family has been shown to protect against a number of degenerative diseases, including severe diseases of the nervous system. The cytoprotective actions of the HSR also include processes involving the lysosomal system, such as cell death, autophagy, and protection against lysosomal membrane permeabilization, and have shown promise in a number of LSDs. This review seeks to describe the emerging understanding of the interplay between these two essential metabolic systems, the lysosomes and the HSR, with a p...

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Section: +mentioning

confidence: 73%

Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Ingemann

Kirkegaard

2014

Journal of Lipid Research

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“…Many previous studies proposed an early induction of LMP by this cytokine, for example via the activation of acid or neutral (FAN) sphingomyelinases, cathepsin B or caspase-8 (Boya and Kroemer, 2008;Blomgran et al, 2007;Guicciardi et al, 2000;Guicciardi et al, 2005;Droga-Mazovec et al, 2008;Werneburg et al, 2002;Werneburg et al, 2004;Gyrd-Hansen et al, 2006;Ullio et al, 2012). How the lysosomal membrane is damaged by these molecules has however not been unveiled so far, although a direct perforation by Bax or Bak (Werneburg et al, 2007, Castino et al, 2009Kagedal et al, 2005;Feldstein et al, 2006) or the implication of ROS (without showing from where they in fact originated) were proposed (Zdolsek et al, 1993;Brunk et al, 1995;Roberg and Ö llinger, 1998;Brunk and Svensson, 1999;Terman et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

TNFα-induced lysosomal membrane permeability (LMP) is downstream of MOMP and triggered by caspase-mediated p75 cleavage and ROS formation

Huai

Vögtle

Jöckel

et al. 2013

Journal of Cell Science

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SummaryWhen NF-kB activation or protein synthesis is inhibited, tumor necrosis factor alpha (TNFa) can induce apoptosis through Bax-and Bak-mediated mitochondrial outer membrane permeabilization (MOMP) leading to caspase-3 activation. Additionally, previous studies have implicated lysosomal membrane permeability (LMP) and formation of reactive oxygen species (ROS) as early steps of TNFainduced apoptosis. However, how these two events connect to MOMP and caspase-3 activation has been largely debated. Here, we present the novel finding that LMP induced by the addition of TNFa plus cycloheximide (CHX), the release of lysosomal cathepsins and ROS formation do not occur upstream but downstream of MOMP and require the caspase-3-mediated cleavage of the p75 NDUFS1 subunit of respiratory complex I. Both a caspase non-cleavable p75 mutant and the mitochondrially localized antioxidant MitoQ prevent LMP mediated by TNFa plus CHX and partially interfere with apoptosis induction. Moreover, LMP is completely blocked in cells deficient in both Bax and Bak, Apaf-1, caspase-9 or both caspase-3 and -7. Thus, after MOMP, active caspase-3 exerts a feedback action on complex I to produce ROS. ROS then provoke LMP, cathepsin release and further caspase activation to amplify TNFa apoptosis signaling.

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“…22 More recently, we have shown that TNF and CHX-induced death is mediated by LMP. 23,24 These findings indicate that, indeed, intralysosomal iron, oxidative stress and LMP all contribute to TNF toxicity. In the present study, we further investigate the role of lysosomal iron and LMP following exposure of rat hepatoma cells to TNF and CHX.…”

Section: Introductionmentioning

confidence: 88%

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

et al. 2015

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, tandem fluorescent microtubule-associated protein 1 light chain 3 A/B (green/red fluorescent proteins chimera); TNFRSF1A/TNFR1, tumor necrosis factor receptor superfamily member 1A; TNFRSF1B/TNFR2, tumor necrosis factor receptor superfamily member 1B.Lysosomal membrane permeabilization (LMP) induced by oxidative stress has recently emerged as a prominent mechanism behind TNF cytotoxicity. This pathway relies on diffusion of hydrogen peroxide into lysosomes containing redox-active iron, accumulated by breakdown of iron-containing proteins and subcellular organelles. Upon oxidative lysosomal damage, LMP allows relocation to the cytoplasm of low mass iron and acidic hydrolases that contribute to DNA and mitochondrial damage, resulting in death by apoptosis or necrosis. Here we investigate the role of lysosomes and free iron in death of HTC cells, a rat hepatoma line, exposed to TNF following metallothionein (MT) upregulation. Iron-binding MT does not normally occur in HTC cells in significant amounts. Intracellular iron chelation attenuates TNF and cycloheximide (CHX)-induced LMP and cell death, demonstrating the critical role of this transition metal in mediating cytokine lethality. MT upregulation, combined with starvation-activated MT autophagy almost completely suppresses TNF and CHX toxicity, while impairment of both autophagy and MT upregulation by silencing of Atg7, and Mt1a and/or Mt2a, respectively, abrogates protection. Interestingly, MT upregulation by itself has little effect, while stimulated autophagy alone depresses cytokine toxicity to some degree. These results provide evidence that intralysosomal iron-catalyzed redox reactions play a key role in TNF and CHX-induced LMP and toxicity. The finding that chelation of intralysosomal iron achieved by autophagic delivery of MT, and to some degree probably of other ironbinding proteins as well, into the lysosomal compartment is highly protective provides a putative mechanism to explain autophagy-related suppression of death by TNF and CHX.

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Sphingosine mediates TNFα-induced lysosomal membrane permeabilization and ensuing programmed cell death in hepatoma cells

Cited by 70 publications

References 45 publications

Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

TNFα-induced lysosomal membrane permeability (LMP) is downstream of MOMP and triggered by caspase-mediated p75 cleavage and ROS formation

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

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