TNF-Induced Activation of the Nox1 NADPH Oxidase and Its Role in the Induction of Necrotic Cell Death

Kim, You‐Sun; Morgan, Michael J.; Choksi, Swati; Liu, Zheng-gang

doi:10.1016/j.molcel.2007.04.021

Cited by 482 publications

(422 citation statements)

References 35 publications

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“…22 TNF activates NADPH oxidase in different cell types. 45,46 In professional The effect of Atg7 silencing on starvation-induced autophagic flux was assayed by transfecting mock-and Atg7-silenced cells with the ptfLC3 construct as described in the legend to Figure 3A. Quantification of autophagosomes and autolysosomes was performed on single-cell images obtained by confocal microscopy.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…Mitochondria, through the generation of ROS, were considered essential for the execution of necroptosis [23][24][25] . To directly test this, we used Parkin-mediated mitophagy to efficiently remove mitochondria and assess its effect on necroptosis and apoptosis.…”

Section: Investigating the Role Of Mitochondria In Cell Deathmentioning

confidence: 99%

Depletion of mitochondria in mammalian cells through enforced mitophagy

et al. 2016

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Mitochondria are not only the "power-house" of the cell, but are also involved in a multitude of processes that include calcium storage, cell-cycle and cell-death. Traditional means to investigate mitochondrial importance in a given cellular process have centred upon depletion of mitochondrial DNA (mtDNA) through chemical or genetic means. While these methods severely disrupt mitochondrial electron transport chain, mtDNA-depleted cells still maintain mitochondria and many mitochondrial functions. Here, we describe a straightforward protocol to generate mammalian cell populations with low to non-detectable levels of mitochondria. Ectopic expression of the ubiquitin E3 ligase Parkin, combined with short-term mitochondrial uncoupler treatment, engages widespread mitophagy, and effectively eliminates mitochondria. In this protocol, we explain how to generate mitochondria-depleted cells and a variety of methods to confirm mitochondrial clearance. Furthermore, we describe culture conditions to maintain mitochondrial-depleted cells with minimal loss of viability for longitudinal studies. This method should prove useful to investigate the importance of mitochondria in a variety of biological processes.

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“…TNF-TNFR complex has also been shown to enhance NADPH oxidase activity promoting a burst of oxidative stress and leading to necrotic cell death (141,142).…”

Section: Cross-linking Of Tnf and Tnfr Type I Dependent Pathwaymentioning

confidence: 99%

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

et al. 2009

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One of the functions of the immune system is to recognize and destroy abnormal or infected cells to maintain homeostasis. This is accomplished by cytotoxic lymphocytes. Cytotoxicity is a highly organized multifactor process. Here, we reviewed the apoptosis pathways induced by the two main cytotoxic lymphocyte subsets, natural killer (NK) cells and CD8 + T cells. In base to recent experimental evidence, we reviewed NK receptors involved in recognition of target-cell, as well as lytic molecules such as perforin, granzymes-A and -B, and granulysin. In addition, we reviewed the Fas-FasL intercellular linkage mediated pathway, and briefly the cross-linking of tumor necrosis factor (TNF) and TNF receptor pathway. We discussed three models of possible molecular interaction between lytic molecules from effector cytotoxic cells and target-cell membrane to induction of apoptosis. Cellular & Molecular Immunology. 2009;6(1):15-25.

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TNF-Induced Activation of the Nox1 NADPH Oxidase and Its Role in the Induction of Necrotic Cell Death

Cited by 482 publications

References 35 publications

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

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

Depletion of mitochondria in mammalian cells through enforced mitophagy

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

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