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.

Monocytic cell necrosis is mediated by potassium depletion and caspase-like proteases

1999 ◽  
Vol 276 (3) ◽  
pp. C717-C724 ◽  
Author(s):  
Michel Warny ◽  
Ciarán P. Kelly
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Cysteine Proteases ◽  
Morphological Features ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Monocytic Cell ◽  
Mitochondrial Permeability

Apoptosis is a physiological cell death that culminates in mitochondrial permeability transition and the activation of caspases, a family of cysteine proteases. Necrosis, in contrast, is a pathological cell death characterized by swelling of the cytoplasm and mitochondria and rapid plasma membrane disruption. Necrotic cell death has long been opposed to apoptosis, but it now appears that both pathways involve mitochondrial permeability transition, raising the question of what mediates necrotic cell death. In this study, we investigated mechanisms that promote necrosis induced by various stimuli ( Clostridium difficile toxins, Staphylococcus aureus alpha toxin, ouabain, nigericin) in THP-1 cells, a human monocytic cell line, and in monocytes. All stimuli induced typical features of necrosis and triggered protease-mediated release of interleukin-1β (IL-1β) and CD14 in both cell types. K+depletion was actively implicated in necrosis because substituting K+for Na+in the extracellular medium prevented morphological features of necrosis and IL-1β release. N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad-spectrum caspase inhibitor, prevented morphological features of necrosis, plasma membrane destruction, loss of mitochondrial membrane potential, IL-1β release, and CD14 shedding induced by all stimuli. Thus, in monocytic cells, necrosis is a cell death pathway mediated by passive K+efflux and activation of caspase-like proteases.

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 Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Jason Karch ◽  
Jennifer Q Kwong ◽  
Adam R Burr ◽  
Michelle A Sargent ◽  
John W Elrod ◽  
...  
Keyword(s):  
Cell Death ◽  
Membrane Permeability ◽  
Outer Membrane ◽  
Mitochondrial Permeability Transition ◽  
Critical Event ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Inner Membrane ◽  
Mitochondrial Permeability ◽  
Outer Membrane Permeability

A critical event in ischemia-based cell death is the opening of the mitochondrial permeability transition pore (MPTP). However, the molecular identity of the components of the MPTP remains unknown. Here, we determined that the Bcl-2 family members Bax and Bak, which are central regulators of apoptotic cell death, are also required for mitochondrial pore-dependent necrotic cell death by facilitating outer membrane permeability of the MPTP. Loss of Bax/Bak reduced outer mitochondrial membrane permeability and conductance without altering inner membrane MPTP function, resulting in resistance to mitochondrial calcium overload and necrotic cell death. Reconstitution with mutants of Bax that cannot oligomerize and form apoptotic pores, but still enhance outer membrane permeability, permitted MPTP-dependent mitochondrial swelling and restored necrotic cell death. Our data predict that the MPTP is an inner membrane regulated process, although in the absence of Bax/Bak the outer membrane resists swelling and prevents organelle rupture to prevent 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 Mitochondrial oxidative stress and cell death in astrocytes —requirement for stored Ca2+ and sustained opening of the permeability transition pore

2002 ◽  
Vol 115 (6) ◽  
pp. 1175-1188 ◽  
Author(s):  
Jake Jacobson ◽  
Michael R. Duchen
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Generation ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Mitochondrial Ros ◽  
Transient Events

The role of oxidative stress is established in a range of pathologies. As mitochondria are a major source of reactive oxygen species (ROS), we have developed a model in which an intramitochondrial photosensitising agent is used to explore the consequences of mitochondrial ROS generation for mitochondrial function and cell fate in primary cells. We have found that, in astrocytes, the interplay between mitochondrial ROS and ER sequestered Ca2+ increased the frequency of transient mitochondrial depolarisations and caused mitochondrial Ca2+ loading from ER stores. The depolarisations were attributable to opening of the mitochondrial permeability transition pore (mPTP). Initially, transient events were seen in individual mitochondria, but ultimately, the mitochondrial potential(Δψm) collapsed completely and irreversibly in the whole population. Both ROS and ER Ca2+ were required to initiate these events, but neither alone was sufficient. Remarkably, the transient events alone appeared innocuous, and caused no increase in either apoptotic or necrotic cell death. By contrast, progression to complete collapse ofΔψ m caused necrotic cell death. Thus increased mitochondrial ROS generation initiates a destructive cycle involving Ca2+ release from stores and mitochondrial Ca2+-loading,which further increases ROS production. The amplification of oxidative stress and Ca2+ loading culminates in opening of the mPTP and necrotic cell death in primary brain cells.

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.

Benzo(a)pyrene-7,8-diol-9,10-epoxide induced p53-independent necrosis via the mitochondria-associated pathway involving Bax and Bak activation

2014 ◽  
Vol 34 (2) ◽  
pp. 179-190 ◽  
Author(s):  
W Zhang ◽  
N Liu ◽  
X Wang ◽  
X Jin ◽  
H Du ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Cytochrome C Release

Benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) is a highly reactive DNA damage agent and can induce cell death through both p53-independent and -dependent pathways. However, little is known about the molecular mechanisms of p53-independent pathways in BPDE-induced cell death. To understand the p53-independent mechanisms, we have now examined BPDE-induced cytotoxicity in p53-deficient baby mouse kidney (BMK) cells. The results showed that BPDE could induce Bax and Bak activation, cytochrome c release, caspases activation, and necrotic cell death in the BMK cells. Bax and Bak, two key molecules of mitochondrial permeability transition pore, were interdependently activated by BPDE, with Bax and Bak translocation to and Bax/Bak homo-oligomerization in mitochondria, release of cytochrome c was induced. Importantly, cytochrome c release and necrotic cell death were diminished in BMK cells (Bax−/−), BMK cells (Bak−/−), and BMK cells (Bax−/−/Bak−/−). Furthermore, overexpression of Bcl-2 could ameliorate BPDE-induced cytochrome c release and necrosis. Together the findings suggested that BPDE-induced necrosis was modulated by the p53-independent pathway, which was related to the translocation of Bax and Bak to mitochondria, release of cytochrome c, and activation of caspases.

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