RIP1-mediated mitochondrial dysfunction and ROS production contributed to tumor necrosis factor alpha-induced L929 cell necroptosis and autophagy

Ye, Yuanchao; Wang, Hongju; Yu, Lu; Tashiro, Shin‐ichi; Onodera, Satoshi; Ikejima, Takashi

doi:10.1016/j.intimp.2012.08.003

Cited by 69 publications

(34 citation statements)

References 36 publications

(41 reference statements)

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“…Previous reports established that zVAD by itself without exogenous addition of TNF-α, induces necroptosis and autophagy in L929 cells via stimulation of autocrine production of TNF-α [15,46,47]. It was proposed that activation of autophagy in this context could be a cellular attempt to survive zVAD-mediated induction of TNF-α necroptotic signaling.…”

Section: Resultsmentioning

confidence: 99%

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Docosahexanoic acid antagonizes TNF-α-induced necroptosis by attenuating oxidative stress, ceramide production, lysosomal dysfunction, and autophagic features

et al. 2014

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Objective It was previously reported that docosahexanoic acid (DHA) reduces TNF-α-induced necrosis in L929 cells. However, the mechanisms underlying this reduction have not been investigated. The present study was designed to investigate cellular and biochemical mechanisms underlying the attenuation of TNF-α-induced necroptosis by DHA in L929 cells. Methods L929 cells were pre-treated with DHA prior to exposure to TNF-α, zVAD, or Necrostatin-1 (Nec-1). Cell death and survival were assessed by MTT and caspase activity assays, and microscopic visualization. Reactive oxygen species (ROS) were measured by flow cytometry. C16- and C18-ceramide were measured by mass spectrometry. Lysosomal membrane permeabilization (LMP) was evaluated by fluorescence microscopy and flow cytometry using Acridine Orange. Cathepsin L activation was evaluated by immunoblotting and fluorescence microscopy. Autophagy was assessed by immunoblotting of LC3-II and Beclin. Results Exposure of L929 cells to TNF-α alone for 24 h induced necroptosis, as evidenced by inhibition of cell death by Nec-1, absence of caspase-3 activity and lamin B cleavage, and morphological analysis. DHA attenuated multiple biochemical events associated with TNF-α-induced necroptosis, including ROS generation, ceramide production, lysosomal dysfunction, cathepsin L activation, and autophagic features. DHA also attenuated zVAD-induced necroptosis but did not attenuate the enhanced apoptosis and necrosis induced by combination of TNF-α with Actinomycin D or zVAD, respectively, suggesting that its protective effects might be limited by the strength of the cell death insult induced by TNF-α. Conclusions DHA effectively attenuates TNF-α-induced necroptosis and autophagy, most likely via its ability to inhibit TNF-α-induced sphingolipid metabolism and oxidative stress. These results highlight the role of this Omega-3 fatty acid in antagonizing inflammatory cell death.

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Section: Resultsmentioning

confidence: 99%

“…It is well established that enhanced ROS-production by mitochondria is a key mediator of TNF-α-induced necroptosis in L929 cells [15,43]. Our group reported previously that DHA attenuates ROS production during neuronal lipotoxicity [33].…”

Section: Resultsmentioning

confidence: 99%

Docosahexanoic acid antagonizes TNF-α-induced necroptosis by attenuating oxidative stress, ceramide production, lysosomal dysfunction, and autophagic features

et al. 2014

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“…[32, 33] Furthermore, mitochondrial dysfunction has been linked with necroptosis, as well. [28, 34, 35] Therefore, we next examined the change of mitochondrial transmembrane potential (MMP, ΔΨm) upon the removal of TC. As shown in Figure 3A, interestingly, the ΔΨm increased after 48 h of TC removal.…”

Section: Resultsmentioning

confidence: 99%

Bivalent Compound 17MN Exerts Neuroprotection through Interaction at Multiple Sites in a Cellular Model of Alzheimer’s Disease

Chojnacki

Wade

et al. 2015

JAD

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Multiple pathogenic factors have been suggested in playing a role in the development of Alzheimer’s disease (AD). The multifactorial nature of AD also suggests the potential use of compounds with polypharmacology as effective disease-modifying agents. Recently, we have developed a bivalent strategy to include cell membrane anchorage into the molecular design. Our results demonstrated that the bivalent compounds exhibited multifunctional properties and potent neuroprotection in a cellular AD model. Herein, we report the mechanistic exploration of one of the representative bivalent compounds, 17MN, in MC65 cells. Our results established that MC65 cells die through a necroptotic mechanism upon the removal of tetracycline (TC). Furthermore, we have shown that mitochondrial membrane potential (MMP) and cytosolic Ca2+ levels are increased upon removal of TC. Our bivalent compound 17MN can reverse such changes and protect MC65 cells from TC removal induced cytotoxicity. The results also suggest that 17MN may function between the Aβ species and RIPK1 in producing its neuroprotection. Colocalization studies employing a fluorescent analog of 17MN and confocal microscopy demonstrated the interactions of 17MN with both mitochondria and endoplasmic reticulum (ER), thus suggesting that 17MN exerts its neuroprotection via a multiple-site mechanism in MC65 cells. Collectively, these results strongly support our original design rationale of bivalent compounds and encourage further optimization of this bivalent strategy to develop more potent analogs as novel disease-modifying agents for AD.

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“…RIP1 and RIP3 are constitutively expressed in untreated cells but during programmed necrosis certain stimuli, such as TNFα, may increase their level of expression (McComb et al, 2012; Ye et al, 2012). Immunoblotting analysis to assess expression of RIP1 and RIP3 and cleavage of PARP and caspase-3 to their active forms showed that RIP1 and RIP3 were constitutively expressed in infected macrophages and that addition of nec-1 did not alter expression levels; cleavage of caspase-3 and PARP began at 10 h pi (Fig.…”

Section: Rip1 and Rip3 Expression During Necroptosismentioning

confidence: 99%

Inhibition of Theiler's virus-induced apoptosis in infected murine macrophages results in necroptosis

Son

Lipton

2015

Virus Research

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In mice Theiler’s murine encephalomyelitis virus (TMEV) persists in macrophages that eventually undergo apoptosis. TMEV infection of macrophages in culture induces apoptosis through the intrinsic pathway, restricting virus yields. We show that inhibition of TMEV-induced apoptosis leads to phosphorylation of receptor interacting protein 1 (RIP1), localization of RIP1 and RIP3 to mitochondria, ROS production independent of MAPK activation and programmed necrosis (necroptosis). Blocking both apoptotis and necroptosis restored virus yields.

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RIP1-mediated mitochondrial dysfunction and ROS production contributed to tumor necrosis factor alpha-induced L929 cell necroptosis and autophagy

Cited by 69 publications

References 36 publications

Docosahexanoic acid antagonizes TNF-α-induced necroptosis by attenuating oxidative stress, ceramide production, lysosomal dysfunction, and autophagic features

Docosahexanoic acid antagonizes TNF-α-induced necroptosis by attenuating oxidative stress, ceramide production, lysosomal dysfunction, and autophagic features

Bivalent Compound 17MN Exerts Neuroprotection through Interaction at Multiple Sites in a Cellular Model of Alzheimer’s Disease

Inhibition of Theiler's virus-induced apoptosis in infected murine macrophages results in necroptosis

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