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.

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.

scholarly journals Impaired NF-κB signalling underlies cyclophilin D-mediated mitochondrial permeability transition pore opening in doxorubicin cardiomyopathy

2019 ◽  
Vol 116 (6) ◽  
pp. 1161-1174 ◽  
Author(s):  
Rimpy Dhingra ◽  
Matthew Guberman ◽  
Inna Rabinovich-Nikitin ◽  
Jonathon Gerstein ◽  
Victoria Margulets ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Cardiac Myocytes ◽  
Gene Activation ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Necrotic Cell Death ◽  
Cyclophilin D ◽  
Necrotic Cell ◽  
Mptp Opening

Abstract Aims The chemotherapy drug doxorubicin (Dox) is commonly used for treating a variety of human cancers; however, it is highly cardiotoxic and induces heart failure. We previously reported that the Bcl-2 mitochondrial death protein Bcl-2/19kDa interaction protein 3 (Bnip3), is critical for provoking mitochondrial perturbations and necrotic cell death in response to Dox; however, the underlying mechanisms had not been elucidated. Herein, we investigated mechanism that drives Bnip3 gene activation and downstream effectors of Bnip3-mediated mitochondrial perturbations and cell death in cardiac myocytes treated with Dox. Methods and results Nuclear factor-κB (NF-κB) signalling, which transcriptionally silences Bnip3 activation under basal states in cardiac myocytes was dramatically reduced following Dox treatment. This was accompanied by Bnip3 gene activation, mitochondrial injury including calcium influx, permeability transition pore (mPTP) opening, loss of nuclear high mobility group protein 1, reactive oxygen species production, and cell death. Interestingly, impaired NF-κB signalling in cells treated with Dox was accompanied by protein complexes between Bnip3 and cyclophilin D (CypD). Notably, Bnip3-mediated mPTP opening was suppressed by inhibition of CypD—demonstrating that CypD functionally operates downstream of Bnip3. Moreover, restoring IKKβ–NF-κB activity in cardiac myocytes treated with Dox suppressed Bnip3 expression, mitochondrial perturbations, and necrotic cell death. Conclusions The findings of the present study reveal a novel signalling pathway that functionally couples NF-κB and Dox cardiomyopathy to a mechanism that is mutually dependent upon and obligatorily linked to the transcriptional control of Bnip3. Our findings further demonstrate that mitochondrial injury and necrotic cell death induced by Bnip3 is contingent upon CypD. Hence, maintaining NF-κB signalling may prove beneficial in reducing mitochondrial dysfunction and heart failure in cancer patients undergoing Dox chemotherapy.

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.

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 Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death

2010 ◽  
Vol 433 (1) ◽  
pp. 119-125 ◽  
Author(s):  
Allison M. McGee ◽  
Christopher P. Baines
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Binding Protein ◽  
Critical Role ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Critical Event ◽  
Mitochondrial Permeability

Opening of the MPT (mitochondrial permeability transition) pore is a critical event in mitochondrial-mediated cell death. However, with the exception of CypD (cyclophilin D), the exact molecular composition of the MPT pore remains uncertain. C1qbp (complement 1q-binding protein) has recently been hypothesized to be an essential component of the MPT pore complex. To investigate whether C1qbp indeed plays a critical role in MPT and cell death, we conducted both gain-of-function and loss-of-function experiments in MEFs (mouse embryonic fibroblasts). We first confirmed that C1qbp is a soluble protein that localizes to the mitochondrial matrix in mouse cells and tissues. Similarly, overexpression of C1qbp in MEFs using an adenovirus resulted in its exclusive localization to mitochondria. To our surprise, increased C1qbp protein levels actually suppressed H2O2-induced MPT and cell death. Antithetically, knockdown of endogenous C1qbp with siRNA (small interfering RNA) sensitized the MEFs to H2O2-induced MPT and cell death. Moreover, we found that C1qbp could directly bind to CypD. Therefore C1qbp appears to act as an endogenous inhibitor of the MPT pore, most likely through binding to CypD, and thus protects cells against oxidative stress.

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