Self-consumption: the interplay of autophagy and apoptosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Marino G
PROVIDER: S-EPMC3970201 | biostudies-literature | 2014 Feb
REPOSITORIES: biostudies-literature
Publications
Self-consumption: the interplay of autophagy and apoptosis.
Mariño Guillermo G Niso-Santano Mireia M Baehrecke Eric H EH Kroemer Guido G
Nature reviews. Molecular cell biology 20140108 2
Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively, and many stress pathways sequentially elicit autophagy, and apoptosis within the same cell. Generally autophagy blocks the induction of apoptosis, and apoptosis-associated caspase activation shuts off the autophagic process. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis or necrosis, and autophagy has been shown to de ...[more]
Similar Datasets
Project description:Malignant gliomas are common primary tumors of the central nervous system. The prognosis of patients with malignant glioma is poor in spite of current intensive therapy and thus novel therapeutic modalities are necessary. Bufalin is the major component of Chan-Su (a traditional Chinese medicine) extracts from the venom of Bufo gargarizan. In this study, we evaluated the growth inhibitory effect of bufalin on glioma cells and explored the underlying molecular mechanisms. Our results showed that bufalin inhibited the growth of glioma cells significantly. Mechanistic studies demonstrated that bufalin induced apoptosis through mitochondrial apoptotic pathway. In addition, bufalin was also found to induce ER stress-mediated apoptosis, which was supported by the up- regulation of ER stress markers, CHOP and GRP78, and augmented phosphorylation of PERK and eIF2? as well as cleavage of caspase-4. Downregulation of CHOP using siCHOP RNA attenuated bufalin-induced apoptosis, further confirming the role of ER stress response in mediating bufalin-induced apoptosis. Evidence of bufalin-induced autophagy included formation of the acidic vesicular organelles, increase of autophagolysosomes and LC3-II accumulation. Further experiments showed that the mechanism of bufalin-induced autophagy associated with ATP deleption involved an increase in the active form of AMPK, decreased phosphorylation levels of mTOR and its downstream targets 4EBP1 and p70S6K1. Furthermore, TUDC and silencing of eIF2? or CHOP partially blocked bufalin-induced accumulation of LC3-II, which indicated that ER stress preceded bufalin-induced autophagy and PERK/eIF2?/CHOP signaling pathway played a major part in the process. Blockage of autophagy increased expression of ER stress associated proteins and the ratio of apoptosis, indicating that autophagy played a cytoprotective role in bufalin induced ER stress and cell death. In conclusion, bufalin inhibits glioma cell growth and induces interplay between apoptosis and autophagy through endoplasmic reticulum stress. It will provide molecular bases for developing bufalin into a drug candidate for the treatment of maglinant glioma.
| S-EPMC3927133 | biostudies-literature
Project description:Programmed cell death is characterized by a cascade of tightly controlled events that culminate in the orchestrated death of the cell. In multicellular organisms autophagy and apoptosis are recognized as two principal means by which these genetically determined cell deaths occur. During plant-microbe interactions cell death programs can mediate both resistant and susceptible events. Via oxalic acid (OA), the necrotrophic phytopathogen Sclerotinia sclerotiorum hijacks host pathways and induces cell death in host plant tissue resulting in hallmark apoptotic features in a time and dose dependent manner. OA-deficient mutants are non-pathogenic and trigger a restricted cell death phenotype in the host that unexpectedly exhibits markers associated with the plant hypersensitive response including callose deposition and a pronounced oxidative burst, suggesting the plant can recognize and in this case respond, defensively. The details of this plant directed restrictive cell death associated with OA deficient mutants is the focus of this work. Using a combination of electron and fluorescence microscopy, chemical effectors and reverse genetics, we show that this restricted cell death is autophagic. Inhibition of autophagy rescued the non-pathogenic mutant phenotype. These findings indicate that autophagy is a defense response in this necrotrophic fungus/plant interaction and suggest a novel function associated with OA; namely, the suppression of autophagy. These data suggest that not all cell deaths are equivalent, and though programmed cell death occurs in both situations, the outcome is predicated on who is in control of the cell death machinery. Based on our data, we suggest that it is not cell death per se that dictates the outcome of certain plant-microbe interactions, but the manner by which cell death occurs that is crucial.
| S-EPMC3623803 | biostudies-literature
Project description:BBC3 (BCL2 binding component 3) is a known apoptosis inducer; however, its role in microglial survival remains poorly understood. In addition to the classical transcription factor TRP53, Mir143 is involved in BBC3 expression at the post-transcriptional level. Here, we identify unique roles of Mir143-BBC3 in mediating microglial survival via the regulation of the interplay between apoptosis and autophagy. Autophagy inhibition accelerated methamphetamine-induced apoptosis, whereas autophagy induction attenuated the decrease in microglial survival. Moreover, anti-Mir143-dependent BBC3 upregulation reversed the methamphetamine-induced decrease in microglial survival via the regulation of apoptosis and autophagy. The in vivo relevance of these findings was confirmed in mouse models, which demonstrated that the microinjection of anti-Mir143 into the hippocampus ameliorated the methamphetamine-induced decrease in microglia as well as that observed in heterozygous Mir143(+/-) mice. These findings provide new insight regarding the specific contributions of Mir143-BBC3 to microglial survival in the context of drug abuse.
| S-EPMC5082785 | biostudies-literature
Project description:Autophagy is a self-eating process of using lysosomes to degrade macromolecular substances (e.g., proteins and organelles) that are damaged, degenerated, or aging. Lipid metabolism is the synthesis and degradation of lipids (e.g., triglycerides, steroids, and phospholipids) to generate energy or produce the structural components of cell membranes. There is a complex interplay between lipid metabolism (e.g., digestion, absorption, catabolism, biosynthesis, and peroxidation) and autophagy machinery, leading to the modulation of cell homeostasis, including cell survival and death. In particular, lipid metabolism is involved in the formation of autophagic membrane structures (e.g., phagophores and autophagosomes) during stress. Moreover, autophagy, especially selective autophagy (e.g., lipophagy, ferritinophagy, clockophagy, and mitophagy), promotes lipid catabolism or lipid peroxidation-induced ferroptosis through the degradation of various substances within the cell. A better understanding of the mechanisms of autophagy and possible links to lipid metabolism will undoubtedly promote potential treatments for a variety of diseases.
| S-EPMC7283384 | biostudies-literature
Project description:Prognosis of patients with glioblastoma (GBM) remains very poor, thus making the development of new drugs urgent. Resveratrol (Rsv) is a natural compound that has several beneficial effects such as neuroprotection and cytotoxicity for several GBM cell lines. Here we evaluated the mechanism of action of Rsv on human GBM cell lines, focusing on the role of autophagy and its crosstalk with apoptosis and cell cycle control. We further evaluated the role of autophagy and the effect of Rsv on GBM Cancer Stem Cells (gCSCs), involved in GBM resistance and recurrence. Glioma cells treated with Rsv was tested for autophagy, apoptosis, necrosis, cell cycle and phosphorylation or expression levels of key players of these processes. Rsv induced the formation of autophagosomes in three human GBM cell lines, accompanied by an upregulation of autophagy proteins Atg5, beclin-1 and LC3-II. Inhibition of Rsv-induced autophagy triggered apoptosis, with an increase in Bax and cleavage of caspase-3. While inhibition of apoptosis or autophagy alone did not revert Rsv-induced toxicity, inhibition of both processes blocked this toxicity. Rsv also induced a S-G2/M phase arrest, accompanied by an increase on levels of pCdc2(Y15), cyclin A, E and B, and pRb (S807/811) and a decrease of cyclin D1. Interestingly, this arrest was dependent on the induction of autophagy, since inhibition of Rsv-induced autophagy abolishes cell cycle arrest and returns the phosphorylation of Cdc2(Y15) and Rb(S807/811), and levels of cyclin A, and B to control levels. Finally, inhibition of autophagy or treatment with Rsv decreased the sphere formation and the percentage of CD133 and OCT4-positive cells, markers of gCSCs. In conclusion, the crosstalk among autophagy, cell cycle and apoptosis, together with the biology of gCSCs, has to be considered in tailoring pharmacological interventions aimed to reduce glioma growth using compounds with multiple targets such as Rsv.
| S-EPMC3113895 | biostudies-literature
Project description:Stroke remains one of the leading causes of permanent disability and death worldwide. Apoptosis and autophagy are two key elements involved in ischemic brain damage. Ethanol is a commonly used and abused chemical substance that affects the prognosis of ischemic stroke. We determined the influence of chronic ethanol consumption on apoptosis and autophagy following transient focal cerebral ischemia. Male C57BL/6 J mice were randomly divided into three groups and gavage fed with 0.7 and 2.8 g/kg/day ethanol or volume-matched water daily for 8 weeks. DNA fragmentation, TUNEL-positive neurons, cleaved caspase-3-positive neurons, translocation of mitochondrial cytochrome C and apoptosis inducing factor (AIF), LC3B-positive neurons, and expression of LC3B, Beclin-1 and Bcl-2 in peri-infarct cortex were evaluated at 24 hours of reperfusion after a 90-minute unilateral middle cerebral artery occlusion (MCAO). Cerebral ischemia/reperfusion (I/R) injury was significantly improved in the 0.7 g/kg/d ethanol group but worsened in the 2.8 g/kg/d ethanol group. DNA fragmentation was significantly increased at 24 hours of reperfusion in all groups. However, the magnitude of the increase was significantly less in the 0.7 g/kg/d ethanol group. In addition, both cleaved caspase-3-positive neurons and TUNEL-positive neurons were significantly less in 0.7 g/kg/d ethanol group. Furthermore, translocation of mitochondrial cytochrome C and AIF was significantly alleviated in the 0.7 g/kg/d ethanol group. On the other hand, baseline expression of LC3B was significantly reduced in the 2.8 g/kg/d ethanol group. Post-ischemic expression of LC3B and LC3B-positive neurons were significantly attenuated in both 0.7 and 2.8 g/kg/d ethanol groups. Moreover, although post-ischemic expression of Beclin-1 was not altered in the ethanol groups, post-ischemic expression of Bcl-2 was significantly greater in both 0.7 and 2.8 g/kg/d ethanol groups. Our findings suggest that light ethanol consumption may protect against cerebral I/R injury by suppressing post-ischemic apoptosis, whereas heavy ethanol consumption may exacerbate cerebral I/R injury by suppressing autophagy.
| S-EPMC7145844 | biostudies-literature
Project description:T-47 cells were treated with rapamycin, 3-methyladenine (3MA)-rapamycin and vehicle (DMSO, control) in a time series manner (1, 8, 24 and 48h), Affymetrix Genechip U133 Plus 2.0 array were used to compare the gene expression patterns of rapamycin-treated, 3MA-rapamycin treated versus control cells. All experiments were carried out in triplicates and a total of 24 chips were used. 3MA-Rapamycin treated samples were only limited to 24 h as total RNA for 48h was degraded.
2012-01-11 | E-MEXP-3487 | biostudies-arrayexpress
Project description:Autophagy to apoptosis switching event is an unexplored area. We were interested to explore the gene expression profile at this juncture. Our Microarray data emphasized that among all eNOS and p62 genes were markedly induced. In fuctional level eNOS expression activates mTORC1 followed by inhibition of autophagy. This ultimately allowed accumulation of p62 . Intraccellular accumulation of p62 sequestered unfolded toxic protein aggregates in mitochondria and ER resulting in to impaired redox regulation. Intraccelular ROS generation further sensitized cells for apoptosis and tilted autophagic response to apoptosis. Cells were treated with Tunicamycin as an inducer of both autophagy and apoptosis. At early stage of Tunicamycin treatment 24h , prostate cancer cell PC3 showed activation of autophagic process where apoptosis was not evident. Sustained ER stress with Tunicamycin induced late apoptoisis at 72h of treatment. Hence we isolated total RNA from Untreated cells, cells with Tunicamycin treatment after 24h and 72h. Further the RNA were used to perform whole genome microarray to analyze the gene expression profile at autophagy and apoptosis juncture. The selected genes were also validated by qPCR and western bot. Morover RNAi study were implemented to evaluate the signaling crosstalk at the juncture of autophagy and apoptosis.
2014-05-22 | E-GEOD-38643 | biostudies-arrayexpress
Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. We found LRRK2 to be degraded in lysosomes by chaperone-mediated autophagy (CMA), whereas the most common pathogenic mutant form of LRRK2, G2019S, was poorly degraded by this pathway. In contrast to the behavior of typical CMA substrates, lysosomal binding of both wild-type and several pathogenic mutant LRRK2 proteins was enhanced in the presence of other CMA substrates, which interfered with the organization of the CMA translocation complex, resulting in defective CMA. Cells responded to such LRRK2-mediated CMA compromise by increasing levels of the CMA lysosomal receptor, as seen in neuronal cultures and brains of LRRK2 transgenic mice, induced pluripotent stem cell-derived dopaminergic neurons and brains of Parkinson's disease patients with LRRK2 mutations. This newly described LRRK2 self-perpetuating inhibitory effect on CMA could underlie toxicity in Parkinson's disease by compromising the degradation of ?-synuclein, another Parkinson's disease-related protein degraded by this pathway.
| S-EPMC3609872 | biostudies-literature
Project description:Due to the critical role played by autophagy in pathogen clearance, pathogens have developed diverse strategies to subvert it. Despite previous key findings of bacteria-autophagy interplay, asystems-level insight into selective targeting by the host and autophagy modulation by the pathogens is lacking. We predicted potential interactions between human autophagy proteins and effector proteins from 56 pathogenic bacterial species by identifying bacterial proteins predicted to have recognition motifs for selective autophagy receptors SQSTM1/p62, CALCOCO2/NDP52 and MAP1LC3/LC3. Using structure-based interaction prediction, we identified bacterial proteins capable to modify core autophagy components. Our analysis revealed that autophagy receptors in general potentially target mostly genus-specific proteins, and not those present in multiple genera. The complementarity between the predicted SQSTM1/p62 and CALCOCO2/NDP52 targets, which has been shown for Salmonella, Listeria and Shigella, could be observed across other pathogens. This complementarity potentially leaves the host more susceptible to chronic infections upon the mutation of autophagy receptors. Proteins derived from enterotoxigenic and non-toxigenic Bacillus outer membrane vesicles indicated that autophagy targets pathogenic proteins rather than non-pathogenic ones. We also observed apathogen-specific pattern as to which autophagy phase could be modulated by specific genera. We found intriguing examples of bacterial proteins that could modulate autophagy, and in turn being targeted by autophagy as ahost defense mechanism. We confirmed experimentally an interplay between a Salmonella protease, YhjJ and autophagy. Our comparative meta-analysis points out key commonalities and differences in how pathogens could affect autophagy and how autophagy potentially recognizes these pathogenic effectors. Abbreviations: ATG5: autophagy related 5; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; GST: glutathione S-transferase; LIR: MAP1LC3/LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3 alpha; OMV: outer membrane vesicles; SQSTM1/p62: sequestosome 1; SCV: Salmonella containing vesicle; TECPR1: tectonin beta-propeller repeat containing 1; YhjJ: hypothetical zinc-protease.
| S-EPMC6693458 | biostudies-literature