scholarly journals Role of the Mitochondrial Signaling Pathway in Murine Coronavirus-Induced Oligodendrocyte Apoptosis

2006 ◽  
Vol 80 (1) ◽  
pp. 395-403 ◽  
Author(s):  
Yin Liu ◽  
Yinghui Pu ◽  
Xuming Zhang
Keyword(s):  
Hepatitis Virus ◽  
Mitochondrial Pathway ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Apoptotic Pathway ◽  
Antiapoptotic Proteins ◽  
Mitochondrial Signaling ◽  
Drastic Increase ◽  
Infected Cells

ABSTRACT A previous study demonstrated that infection of rat oligodendrocytes by mouse hepatitis virus (MHV) resulted in apoptosis, which is caspase dependent (Y. Liu, Y. Cai, and X. Zhang, J. Virol. 77:11952-11963, 2003). Here we determined the involvement of the mitochondrial pathway in MHV-induced oligodendrocyte apoptosis. We found that caspase-9 activity was 12-fold higher in virus-infected cells than in mock-infected cells at 24 h postinfection (p.i.). Pretreatment of cells with a caspase-9 inhibitor completely blocked caspase-9 activation and partially inhibited the apoptosis mediated by MHV infection. Analyses of cytochrome c release further revealed an activation of the mitochondrial apoptotic pathway. Stable overexpression of the two antiapoptotic proteins Bcl-2 and Bcl-xL significantly, though only partially, blocked apoptosis, suggesting that activation of the mitochondrial pathway is partially responsible for the apoptosis. To identify upstream signals, we determined caspase-8 activity, cleavage of Bid, and expression of Bax and Bad by Western blotting. We found a drastic increase in caspase-8 activity and cleavage of Bid at 24 h p.i. in virus-infected cells, suggesting that Bid may serve as a messenger to relay the signals from caspase-8 to mitochondria. However, treatment with a caspase-8 inhibitor only slightly blocked cytochrome c release from the mitochondria. Furthermore, we found that Bax but not Bad was significantly increased at 12 h p.i. in cells infected with both live and UV-inactivated viruses and that Bax activation was partially blocked by treatment with the caspase-8 inhibitor. These results thus establish the involvement of the mitochondrial pathway in MHV-induced oligodendrocyte apoptosis.

scholarly journals Vaccinia Virus Infection Disarms the Mitochondrion-Mediated Pathway of the Apoptotic Cascade by Modulating the Permeability Transition Pore

2001 ◽  
Vol 75 (23) ◽  
pp. 11437-11448 ◽  
Author(s):  
Shawn T. Wasilenko ◽  
Adrienne F. A. Meyers ◽  
Kathleen Vander Helm ◽  
Michele Barry
Keyword(s):  
Virus Infection ◽  
Vaccinia Virus ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Jurkat Cells ◽  
Caspase 8 ◽  
Apoptotic Pathway ◽  
Vaccinia Virus Infection ◽  
Infected Cells ◽  
Apoptotic Cascade

ABSTRACT Many viruses have evolved strategies that target crucial components within the apoptotic cascade. One of the best studied is the caspase 8 inhibitor, crmA/Spi-2, encoded by members of the poxvirus family. Since many proapoptotic stimuli induce apoptosis through a mitochondrion-dependent, caspase 8-independent pathway, we hypothesized that vaccinia virus would encode a mechanism to directly modulate the mitochondrial apoptotic pathway. In support of this, we observed that Jurkat cells, which undergo Fas-mediated apoptosis exclusively through the mitochondrial route, were resistant to Fas-induced death following infection with a crmA/Spi-2-deficient strain of vaccinia virus. In addition, vaccinia virus-infected cells subjected to the proapoptotic stimulus staurosporine exhibited decreased levels of both cytochromec released from the mitochondria and caspase 3 activation. In all cases we found that the loss of the mitochondrial membrane potential, which occurs as a result of opening the multimeric permeability transition pore complex, was prevented in vaccinia virus-infected cells. Moreover, vaccinia virus infection specifically inhibited opening of the permeability transition pore following treatment with the permeability transition pore ligand atractyloside and t-butylhydroperoxide. These studies indicate that vaccinia virus infection directly impacts the mitochondrial apoptotic cascade by influencing the permeability transition pore.

The role of caspase-8, caspase-9, and apoptosis inducing factor in periodontal disease

2018 ◽  
Vol 90 (3) ◽  
pp. 288-294 ◽  
Author(s):  
Kübra Aral ◽  
Cüneyt Asım Aral ◽  
Yvonne Kapila
Keyword(s):  
Periodontal Disease ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Apoptosis Inducing Factor

scholarly journals Mannheimia haemolytica Leukotoxin Induces Apoptosis of Bovine Lymphoblastoid Cells (BL-3) via a Caspase-9-Dependent Mitochondrial Pathway

2005 ◽  
Vol 73 (9) ◽  
pp. 5504-5513 ◽  
Author(s):  
Dhammika N. Atapattu ◽  
Charles J. Czuprynski
Keyword(s):  
Mitochondrial Membrane ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Pathway ◽  
Mannheimia Haemolytica ◽  
Scanning Electron Micrographs ◽  
Caspase 9 ◽  
Lymphoblastoid Cells ◽  
Antiapoptotic Proteins ◽  
Important Virulence Factor

ABSTRACT Mannheimia haemolytica is a key pathogen in the bovine respiratory disease complex. It produces a leukotoxin (LKT) that is an important virulence factor, causing cell death in bovine leukocytes. The LKT binds to the β2 integrin CD11a/CD18, which usually activates signaling pathways that facilitate cell survival. In this study, we investigated mechanisms by which LKT induces death in bovine lymphoblastoid cells (BL-3). Incubation of BL-3 cells with a low concentration of LKT results in the activation of caspase-3 and caspase-9 but not caspase-8. Similarly, the proapoptotic proteins Bax and BAD were significantly elevated, while the antiapoptotic proteins Bcl-2, BclXL and Akt-1 were downregulated. Following exposure to LKT, we also observed a reduction in mitochondrial cytochrome c and corresponding elevation of cytosolic cytochrome c, suggesting translocation from the mitochondrial compartment to the cytosol. Consistent with this observation, tetramethylrhodamine ethyl ester perchlorate staining revealed that mitochondrial membrane potential was significantly reduced. These data suggest that LKT induces apoptosis of BL-3 cells via a caspase-9-dependent mitochondrial pathway. Furthermore, scanning electron micrographs of mitochondria from LKT-treated BL-3 cells revealed lesions in the outer mitochondrial membrane, which are larger than previous reports of the permeability transition pore through which cytochrome c is usually released.

scholarly journals The mitochondrial pathway of apoptosis is triggered during feline calicivirus infection

2006 ◽  
Vol 87 (2) ◽  
pp. 357-361 ◽  
Author(s):  
Alessandro Natoni ◽  
George E. N. Kass ◽  
Michael J. Carter ◽  
Lisa O. Roberts
Keyword(s):  
Caspase 3 ◽  
Chromatin Condensation ◽  
Mitochondrial Pathway ◽  
Feline Calicivirus ◽  
Upper Respiratory Tract ◽  
Caspase 9 ◽  
The Family ◽  
Infected Cells ◽  
Upper Respiratory ◽  
Subsequent Activation

Feline calicivirus (FCV) belongs to the family Caliciviridae and is an important pathogen of the upper respiratory tract of cats. Recent studies have shown that cells infected with FCV undergo apoptosis, as evidenced by caspase activation, chromatin condensation and cleavage of poly(ADP-ribose) polymerase. Here, the upstream events were investigated in order to define the molecular mechanism of apoptosis in FCV-infected cells. It was shown that FCV induced translocation of phosphatidylserine to the cell outer membrane and release of cytochrome c from mitochondria at about 6–8 h post-infection. These events were preceded by the loss of mitochondrial membrane potential and Bax translocation from the cytosol to mitochondria between 4 and 6 h after infection. Release of cytochrome c from mitochondria triggered the activation of caspase-9 and the subsequent activation of the executioner caspase, caspase-3. These results suggest that the mitochondrial pathway of apoptosis is triggered during FCV infection.

scholarly journals Plant Food Anthocyanins Induced Platelet Apoptosis Via BCL-2/BCL-XL Pathway

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4988-4988
Author(s):  
Yang Yan ◽  
Ma Jing ◽  
Tian Jinju ◽  
Chen Liyi ◽  
Songmei Yin ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Caspase 3 ◽  
Caspase 8 ◽  
Plant Food ◽  
Intrinsic Apoptotic Pathway ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Platelet Apoptosis ◽  
Activated Platelets

Abstract Background: Platelets are versatile cells and play important roles in hemostasis/thrombosis, inflammation, and atherosclerosis. The pathogenesis of cardiovascular diseases (CVDs) is linked to platelet hyperactivity which is considered an independent risk factor for CVDs. Platelets are critical for promoting the progression of CVDs, and platelet apoptosis have been reported to be involved in platelet activation. Anthocyanins are major phytochemicals abundant in plant food and have been shown to play a protective role against CVDs. Our previous studies demonstrated that anthocyanins from plant food significantly inhibited platelet activation, adhesion, aggregation and granule secretion, as well as attenuated thrombus growth at both arterial and venous shear stresses in vitro and in vivo, however, the effects of anthocyanin on platelet apoptosis and its mechanisms have not been explored. In the present study, we examined whether anthocyanin Cyanidin-3-glucoside (Cy-3-g) affect platelet apoptosis and the BCL-2/BCL-XL intrinsic apoptotic pathway. Methods: Cy-3-g, the predominant bioactive compound of anthocyanin preparations, was obtained from Polyphenol AS Company in Norway.Purified gel-filtered platelets from healthy volunteers were incubated at 37oC for 40 minutes with different concentrations of Cy-3-g (0.5、5、50μM) or PBS buffer as a control. the activated platelets were triggered with 0.5U thrombin for 15min to induce apoptosis. Mitochondria membrane potential (Δψm) and membrane phospholipid phosphatidylserine (PS) exposure in both activated and resting platelets were assessed by flow cytometry. Cytochrome C release, activation of caspase-3, caspase-8, caspase-9, cleavage of gelsolin, the levels of anti-apoptotic BCL-2 family proteins such as BCL-2, BCL-XL and proapoptotic BCL-2 family proteins Bax, Bak, Bad, Bid and tBid in both activated and resting platelets were measured by western blotting. Results: Cy-3-g at 5μM and 50μM directly induced significant ΔΨm dissipation in activated platelets dose dependently. Correspondingly, 50μM Cy-3-g increased cytochrome C release compared to control. The expression of pro-caspase-8 and pro-caspase-9 decreased, activation of caspase-3, caspase-8 and caspase-9 was induced in activated platelets in both 5μM and 50μM Cy-3-g groups. Both PS exposure and the cleavage of gelsolin increased in activated platelets, however these effects were only observed at Cy-3-g doses as high as 50μM. Cy-3-g did not induce the above changes in resting platelets. The intrinsic apoptotic pathway was initiated by Cy-3-g treatment in activated platelets; Cy-3-g significantly inhibited the expression of BCL-2, BCL-XL and increased the levels of Bax, Bak, Bad and Bid in activated platelets dose dependently. No significant difference was observed in resting platelets. Conclusions: Our data demonstrate for the first time that purified anthocyanin Cy-3-g directly accelerated apoptosis in activated platelets via the BCL-2/BCL-XL pathway. Anthocyanins may possess therapeutic potential for patients suffering from thrombotic conditions. Disclosures No relevant conflicts of interest to declare.

Antibodies to TRAIL Receptors R1 and R2 Induce Apoptosis in Non-Hodgkin’s Lymphoma Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3290-3290 ◽  
Author(s):  
Mitchell Reed Smith ◽  
Fang Jin ◽  
Indira Joshi
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Lines ◽  
Therapeutic Potential ◽  
Specific Inhibitor ◽  
Annexin V ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Apoptotic Pathway ◽  
Curative Therapy ◽  
Trail Receptors

Abstract Monoclonal antibodies and chemotherapy can be effective, but not curative, therapy for non-Hodgkin s lymphoma (NHL). Rituximab acts by several mechanisms, including directly signaling apoptosis of CD20+ cells via the mitochondrial pathway involving caspase 9. Chemotherapy also activates this apoptotic pathway. TRAIL-R1 and -R2 signaling induces apoptosis via a pathway that activates caspase 8. Thus, we investigated the effects of agonistic monoclonal antibodies to TRAIL-R1 and -R2 on NHL cell lines (DoHH2, WSU-FSCCL and FC-TxFL2, each t(14;18)+, EBV-). TRAIL-R1 (HGS-ETR1) and -R2 (HGS-ETR2) antibodies were from Human Genome Sciences (Rockville, MD). FC-TxFL2 expressed the highest cell surface levels of TRAIL-R1 (DR4, target of HGS-ETR1) and TRAIL-R2 (DR5, target of HGS-ETR2). WSU-FSCCL expressed lower, but significant, levels of each. DoHH2 expressed dim TRAIL-R1 and the lowest levels of TRAIL-R2 of the 3 cell lines. IC50 (MTT assay after 72 hr incubation with antibody) was 0.25mcg/ml for WSU-FSCCL and FC-TxFL2 with either HGS-ETR1 or HGS-ETR2, while DoHH2 was minimally inhibited by either antibody. Both HGS-ETR1 and HGS-ETR2 antibodies induced dose dependent increases in apoptosis (annexin V assay) of WSU-FSCCL and FC-TxFL-2, but not DoHH2. Caspase activation (flow cytometry using fluorescent substrates; Western analysis) was seen 4–6 hr after antibody addition. As expected, caspases 3 and 8 were activated by both antibodies in the two sensitive cell lines. Caspase 9, however, was also activated. Thus, TRAIL-R1 and TRAIL-R2 antibody binding inhibits growth, induces apoptosis and activates caspases 3, 8 and 9 in NHL cells expressing the targets. The induction of caspase 9 suggests cross-talk between the extrinsic and intrinsic pathways, in which activation of caspase 8 leads to cleavage and translocation of bid, which in turn leads to activation of caspase 9, and ultimately caspase 3. We have confirmed that bid cleavage does occur in these NHL cells after HGS-ETR1 and HGS-ETR2 binding. We have further shown that both the pan-caspase inhibitor ZVAD and a specific caspase 8 inhibitor block HGS-ETR1 and HGS-ETR2 induced apoptosis. As predicted, a specific inhibitor of caspase 9 only partially blocks apoptosis. This suggests that combination of the agonist HGS-ETR1 and HGS-ETR2 antibodies with agents that act via the caspase 9 pathway would be rational combinations to test for therapeutic potential in NHL.

scholarly journals Flavonoids and Mitochondria: Activation of Cytoprotective Pathways?

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3060 ◽  
Author(s):  
Anna Kicinska ◽  
Wieslawa Jarmuszkiewicz
Keyword(s):  
Cellular Response ◽  
Plant Secondary Metabolites ◽  
Atp Synthesis ◽  
Apoptotic Pathway ◽  
Beneficial Effects ◽  
Natural Substances ◽  
Mitochondrial Signaling ◽  
End Effectors ◽  
Reactive Oxygen Species Signaling

A large number of diverse mechanisms that lead to cytoprotection have been described to date. Perhaps, not surprisingly, the role of mitochondria in these phenomena is notable. In addition to being metabolic centers, due to their role in cell catabolism, ATP synthesis, and biosynthesis these organelles are triggers and/or end-effectors of a large number of signaling pathways. Their role in the regulation of the intrinsic apoptotic pathway, calcium homeostasis, and reactive oxygen species signaling is well documented. In this review, we aim to characterize the prospects of influencing cytoprotective mitochondrial signaling routes by natural substances of plant origin, namely, flavonoids (e.g., flavanones, flavones, flavonols, flavan-3-ols, anthocyanidins, and isoflavones). Flavonoids are a family of widely distributed plant secondary metabolites known for their beneficial effects on human health and are widely applied in traditional medicine. Their pharmacological characteristics include antioxidative, anticarcinogenic, anti-inflammatory, antibacterial, and antidiabetic properties. Here, we focus on presenting mitochondria-mediated cytoprotection against various insults. Thus, the role of flavonoids as antioxidants and modulators of antioxidant cellular response, apoptosis, mitochondrial biogenesis, autophagy, and fission and fusion is reported. Finally, an emerging field of flavonoid-mediated changes in the activity of mitochondrial ion channels and their role in cytoprotection is outlined.

scholarly journals Caspase-8 and Apaf-1-independent Caspase-9 Activation in Sendai Virus-infected Cells

2002 ◽  
Vol 277 (33) ◽  
pp. 29817-29824 ◽  
Author(s):  
Michael Bitzer ◽  
Sorin Armeanu ◽  
Florian Prinz ◽  
Guy Ungerechts ◽  
Wolfgang Wybranietz ◽  
...  
Keyword(s):  
Sendai Virus ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Infected Cells

scholarly journals Rapid Apoptosis Induced by Shiga Toxin in HeLa Cells

2003 ◽  
Vol 71 (5) ◽  
pp. 2724-2735 ◽  
Author(s):  
Jun Fujii ◽  
Takashi Matsui ◽  
Daniel P. Heatherly ◽  
Kailo H. Schlegel ◽  
Peter I. Lobo ◽  
...  
Keyword(s):  
Dna Fragmentation ◽  
Hela Cells ◽  
Shiga Toxin ◽  
Specific Inhibitor ◽  
Mitochondrial Pathway ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Mitochondrial Membranes ◽  
Caspase 9 ◽  
Induced Apoptosis

ABSTRACT Apoptosis was induced rapidly in HeLa cells after exposure to bacterial Shiga toxin (Stx1 and Stx2; 10 ng/ml). Approximately 60% of HeLa cells became apoptotic within 4 h as detected by DNA fragmentation, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and electron microscopy. Stx1-induced apoptosis required enzymatic activity of the Stx1A subunit, and apoptosis was not induced by the Stx2B subunit alone or by the anti-globotriaosylceramide antibody. This activity was also inhibited by brefeldin A, indicating the need for toxin processing through the Golgi apparatus. The intracellular pathway leading to apoptosis was further defined. Exposure of HeLa cells to Stx1 activated caspases 3, 6, 8, and 9, as measured both by an enzymatic assay with synthetic substrates and by detection of proteolytically activated forms of these caspases by Western immunoblotting. Preincubation of HeLa cells with substrate inhibitors of caspases 3, 6, and 8 protected the cells against Stx1-dependent apoptosis. These results led to a more detailed examination of the mitochondrial pathway of apoptosis. Apoptosis induced by Stx1 was accompanied by damage to mitochondrial membranes, measured as a reduced mitochondrial membrane potential, and increased release of cytochrome c from mitochondria at 3 to 4 h. Bid, an endogenous protein known to permeabilize mitochondrial membranes, was activated in a Stx1-dependent manner. Caspase-8 is known to activate Bid, and a specific inhibitor of caspase-8 prevented the mitochondrial damage. Although these data suggested that caspase-8-mediated cleavage of Bid with release of cytochrome c from mitochondria and activation of caspase-9 were responsible for the apoptosis, preincubation of HeLa cells with a specific inhibitor of caspase-9 did not protect against apoptosis. These results were explained by the discovery of a simultaneous Stx1-dependent increase in endogenous XIAP, a direct inhibitor of caspase-9. We conclude that the primary pathway of Stx1-induced apoptosis and DNA fragmentation in HeLa cells is unique and includes caspases 8, 6, and 3 but is independent of events in the mitochondrial pathway.

scholarly journals Redundant role of the cytochrome c-mediated intrinsic apoptotic pathway in pancreatic β-cells

2011 ◽  
Vol 210 (3) ◽  
pp. 285-292 ◽  
Author(s):  
Diana Choi ◽  
Stephanie A Schroer ◽  
Shun Yan Lu ◽  
Erica P Cai ◽  
Zhenyue Hao ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Apoptosis ◽  
Caspase 8 ◽  
Intrinsic Apoptotic Pathway ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Apoptotic Pathway ◽  
Redundant Role

Cytochrome c is one of the central mediators of the mitochondrial or the intrinsic apoptotic pathway. Mice harboring a ‘knock-in’ mutation of cytochrome c, impairing only its apoptotic function, have permitted studies on the essential role of cytochrome c-mediated apoptosis in various tissue homeostasis. To this end, we examined the role of cytochrome c in pancreatic β-cells under homeostatic conditions and in diabetes models, including those induced by streptozotocin (STZ) and c-Myc. Previous studies have shown that both STZ- and c-Myc-induced β-cell apoptosis is mediated through caspase-3 activation; however, the precise mechanism in these modes of cell death was not characterized. The results of our study show that lack of functional cytochrome c does not affect glucose homeostasis or pancreatic β-cell mass under basal conditions. Moreover, the cytochrome c-mediated intrinsic apoptotic pathway is required for neither STZ- nor c-Myc-induced β-cell death. We also observed that the extrinsic apoptotic pathway mediated through caspase-8 was not essential in c-Myc-induced β-cell destruction. These findings suggest that cytochrome c is not required for STZ-induced β-cell apoptosis and, together with the caspase-8-mediated extrinsic pathway, plays a redundant role in c-Myc-induced β-cell apoptosis.

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