scholarly journals Arachidonic Acid Causes Cell Death through the Mitochondrial Permeability Transition

2000 ◽  
Vol 276 (15) ◽  
pp. 12035-12040 ◽  
Author(s):  
Luca Scorrano ◽  
Daniele Penzo ◽  
Valeria Petronilli ◽  
Francesco Pagano ◽  
Paolo Bernardi
Keyword(s):  
Cell Death ◽  
Arachidonic Acid ◽  
Tumor Necrosis ◽  
Aristolochic Acid ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Factor Α ◽  
Necrosis Factor

We have investigated the effects of arachidonic and palmitic acids in isolated rat liver mitochondria and in rat hepatoma MH1C1 cells. We show that both compounds induce the mitochondrial permeability transition (PT). At variance from palmitic acid, however, arachidonic acid causes a PT at concentrations that do not cause PT-independent depolarization or respiratory inhibition, suggesting a specific effect on the PT pore. When added to intact MH1C1 cells, arachidonic acid but not palmitic acid caused a mitochondrial PTin situthat was accompanied by cytochromecrelease and rapidly followed by cell death. All these effects of arachidonic acid could be prevented by cyclosporin A but not by the phospholipase A2inhibitor aristolochic acid. In contrast, tumor necrosis factor α caused phospholipid hydrolysis, induction of the PT, cytochromecrelease, and cell death that could be inhibited by both cyclosporin A and aristolochic acid. These findings suggest that arachidonic acid produced by cytosolic phospholipase A2may be a mediator of tumor necrosis factor α cytotoxicityin situthrough induction of the mitochondrial PT.

scholarly journals The Mitochondrial Permeability Transition Is Required for Tumor Necrosis Factor Alpha-Mediated Apoptosis and Cytochrome c Release

1998 ◽  
Vol 18 (11) ◽  
pp. 6353-6364 ◽  
Author(s):  
Cynthia A. Bradham ◽  
Ting Qian ◽  
Konrad Streetz ◽  
Christian Trautwein ◽  
David A. Brenner ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Necrosis ◽  
Caspase 3 ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Necrosis Factor Alpha ◽  
Mitochondrial Permeability ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT This study assesses the controversial role of the mitochondrial permeability transition (MPT) in apoptosis. In primary rat hepatocytes expressing an IκB superrepressor, tumor necrosis factor alpha (TNFα) induced apoptosis as shown by nuclear morphology, DNA ladder formation, and caspase 3 activation. Confocal microscopy showed that TNFα induced onset of the MPT and mitochondrial depolarization beginning 9 h after TNFα treatment. Initially, depolarization and the MPT occurred in only a subset of mitochondria; however, by 12 h after TNFα treatment, virtually all mitochondria were affected. Cyclosporin A (CsA), an inhibitor of the MPT, blocked TNFα-mediated apoptosis and cytochrome c release. Caspase 3 activation, cytochrome c release, and apoptotic nuclear morphological changes were induced after onset of the MPT and were prevented by CsA. Depolarization and onset of the MPT were blocked in hepatocytes expressing ΔFADD, a dominant negative mutant of Fas-associated protein with death domain (FADD), or crmA, a natural serpin inhibitor of caspases. In contrast, Asp-Glu-Val-Asp-cho, an inhibitor of caspase 3, did not block depolarization or onset of the MPT induced by TNFα, although it inhibited cell death completely. In conclusion, the MPT is an essential component in the signaling pathway for TNFα-induced apoptosis in hepatocytes which is required for both cytochrome c release and cell death and functions downstream of FADD and crmA but upstream of caspase 3.

scholarly journals The Cytotoxicity of Tumor Necrosis Factor Depends on Induction of the Mitochondrial Permeability Transition

1996 ◽  
Vol 271 (47) ◽  
pp. 29792-29798 ◽  
Author(s):  
John G. Pastorino ◽  
Gabriella Simbula ◽  
Kazuhiko Yamamoto ◽  
Peter A. Glascott ◽  
Ronald J. Rothman ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Necrosis Factor

V. Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis

1999 ◽  
Vol 276 (1) ◽  
pp. G1-G6 ◽  
Author(s):  
John J. Lemasters
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Necrotic Cell Death ◽  
Causative Role ◽  
Necrotic Cell ◽  
Mitochondrial Permeability ◽  
Acute Cytotoxicity ◽  
Induced Apoptosis ◽  
Factor Α

Opening of a high-conductance pore conducting solutes of molecular mass <1,500 Da causes onset of the mitochondrial permeability transition (MPT). Cyclosporin A blocks this pore and prevents acute necrotic cell death in several models. Confocal microscopy directly visualizes onset of the MPT during acute cytotoxicity from the movement of the green-fluorescing fluorophore, calcein, into the mitochondria from the cytosol. The MPT also plays a causative role in tumor necrosis factor-α-induced apoptosis in hepatocytes. Progression to apoptosis or necrosis after the MPT may depend on the presence or absence, respectively, of ATP. Often, features of both apoptotic and necrotic cell death develop after death signals and toxic stresses. The term “necrapoptosis” is introduced to emphasize the shared pathways leading to both forms of cell death.

scholarly journals Adenine Nucleotide (ADP/ATP) Translocase 3 Participates in the Tumor Necrosis Factor–induced Apoptosis of MCF-7 Cells

2007 ◽  
Vol 18 (11) ◽  
pp. 4681-4689 ◽  
Author(s):  
Ziqiang Yang ◽  
Wei Cheng ◽  
Lixin Hong ◽  
Wanze Chen ◽  
Yanhai Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Necrosis Factor ◽  
Mcf 7

Mitochondrial adenine nucleotide translocase (ANT) is believed to be a component or a regulatory component of the mitochondrial permeability transition pore (mtPTP), which controls mitochondrial permeability transition during apoptosis. However, the role of ANT in apoptosis is still uncertain, because hepatocytes isolated from ANT knockout and wild-type mice are equally sensitive to TNF- and Fas-induced apoptosis. In a screen for genes required for tumor necrosis factor α (TNF-α)-induced apoptosis in MCF-7 human breast cancer cells using retrovirus insertion–mediated random mutagenesis, we discovered that the ANT3 gene is involved in TNF-α–induced cell death in MCF-7 cells. We further found that ANT3 is selectively required for TNF- and oxidative stress–induced cell death in MCF-7 cells, but it is dispensable for cell death induced by several other inducers. This data supplements previous data obtained from ANT knockout studies, indicating that ANT is involved in some apoptotic processes. We found that the resistance to TNF-α–induced apoptosis observed in ANT3 mutant (ANT3mut) cells is associated with a deficiency in the regulation of the mitochondrial membrane potential and cytochrome c release. It is not related to intracellular ATP levels or survival pathways, supporting a previous model in which ANT regulates mtPTP. Our study provides genetic evidence supporting a role of ANT in apoptosis and suggests that the involvement of ANT in cell death is cell type– and stimulus-dependent.

scholarly journals The Mitochondrial Permeability Transition, Release of Cytochromecand Cell Death

2000 ◽  
Vol 276 (15) ◽  
pp. 12030-12034 ◽  
Author(s):  
Valeria Petronilli ◽  
Daniele Penzo ◽  
Luca Scorrano ◽  
Paolo Bernardi ◽  
Fabio Di Lisa
Keyword(s):  
Cell Death ◽  
Arachidonic Acid ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Link Type ◽  
Open Time ◽  
Pore Opening ◽  
The Relationship

We investigated the relationship between opening of the permeability transition pore (PTP), mitochondrial depolarization, cytochromecrelease, and occurrence of cell death in rat hepatoma MH1C1 cells. Treatment with arachidonic acid orA23187induces PTP openingin situwith similar kinetics, as assessed by the calcein loading-Co2+quenching technique (Petronilli, V., Miotto, G., Canton, M., Colonna, R., Bernardi, P., and Di Lisa, F. (1999)Biophys. J.76, 725–734). Yet depolarization, as assessed from the changes of mitochondrial tetramethylrhodamine methyl ester (TMRM) fluorescence, is rapid and extensive with arachidonic acid and slow and partial withA23187. Cyclosporin A-inhibitable release of cytochromecand cell death correlate with the changes of TMRM fluorescence but not with those of calcein fluorescence. Since pore opening must be accompanied by depolarization, we conclude that short PTP openings are detected only by trapped calcein and may have little impact on cell viability, while changes of TMRM distribution require longer PTP openings, which cause release of cytochromecand may result in cell death. Modulation of the open time appears to be the key element in determining the outcome of stimuli that converge on the PTP.

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