scholarly journals High susceptibility of activated lymphocytes to oxidative stress-induced cell death

2008 ◽  
Vol 80 (1) ◽  
pp. 137-148 ◽  
Author(s):  
Giovanna R. Degasperi ◽  
Roger F. Castilho ◽  
Anibal E. Vercesi
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cyclosporin A ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Iron Chelator ◽  
Activated Lymphocytes ◽  
Mitochondrial Permeability ◽  
Spleen Lymphocytes

The present study provides evidence that activated spleen lymphocytes from Walker 256 tumor bearing rats are more susceptible than controls to tert-butyl hydroperoxide (t-BOOH)-induced necrotic cell death in vitro. The iron chelator and antioxidant deferoxamine, the intracellular Ca2+ chelator BAPTA, the L-type Ca2+ channel antagonist nifedipine or the mitochondrial permeability transition inhibitor cyclosporin A, but not the calcineurin inhibitor FK-506, render control and activated lymphocytes equally resistant to the toxic effects of t-BOOH. Incubation of activated lymphocytes in the presence of t-BOOH resulted in a cyclosporin A-sensitive decrease in mitochondrial membrane potential. These results indicate that the higher cytosolic Ca2+ level in activated lymphocytes increases their susceptibility to oxidative stress-induced cell death in a mechanism involving the participation of mitochondrial permeability transition.

The mitochondrial permeability transition: its molecular mechanism and role in reperfusion injury

1999 ◽  
Vol 66 ◽  
pp. 181-203 ◽  
Author(s):  
Andrew P. Halestrap
Keyword(s):  
Oxidative Stress ◽  
Cyclosporin A ◽  
Reperfusion Injury ◽  
Molecular Mechanism ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Apoptotic Cell ◽  
Heart Function ◽  
Permeability Transition ◽  
Mitochondrial Permeability

The mitochondrial permeability transition (mPT) involves the opening of a non-specific pore in the inner membrane of mitochondria, converting them from organelles whose production of ATP sustains the cell, to instruments of death. Here, I first summarize the evidence in favour of our model for the molecular mechanism of the mPT. It is proposed that the adenine nucleotide translocase (ANT) is converted into a non-specific pore through a calcium-mediated conformational change. This requires the binding of a unique cyclophilin (cyclophilin-D, CyP-D) to the ANT, except when matrix [Ca2+] is very high. Binding of CyP-D is increased in response to oxidative stress and some thiol reagents which sensitize the mPT to [Ca2+]. Matrix adenine nucleotides decrease the sensitivity of the mPT to [Ca2+] by binding to the ANT. This is antagonized by carboxyatractyloside (an inhibitor of the ANT) and by modification of specific thiol groups on the ANT by oxidative stress or thiol reagents; such treatments thus enhance the mPT. In contrast, decreasing intracellular pH below 7.0 greatly desensitizes the mPT to [Ca2+]. Conditions which sensitize the mPT towards [Ca2+] are found in hearts reperfused after a period of ischaemia, a process that may irreversibly damage the heart (reperfusion injury). We have demonstrated directly that mPT pores open during reperfusion (but not ischaemia) using a technique that involves entrapment of [3H]deoxyglucose in mitochondria that have undergone the mPT. The mPT may subsequently reverse in hearts that recover from ischaemia/reperfusion, the extent of resealing correlating with recovery of heart function. A variety of agents that antagonize the mPT protect the heart from reperfusion injury, including cyclosporin A, pyruvate and propofol. Mitochondria that undergo the mPT and then reseal may cause cytochrome c release and thus initiate apoptosis in cells subjected to stresses less severe than those causing necrosis. An example is the apoptotic cell death in the hippocampus that occurs several days after insulin-induced hypoglycaemia, and can be prevented by prior treatment with cyclosporin A.

Confocal microscopy of the mitochondrial permeability transition in necrotic and apoptotic cell death

1999 ◽  
Vol 66 ◽  
pp. 205-222 ◽  
Author(s):  
John J. Lemasters ◽  
Ting Qian ◽  
Lawrence C. Trost ◽  
Brian Herman ◽  
Wayne E. Cascio ◽  
...  
Keyword(s):  
Cell Death ◽  
Confocal Microscopy ◽  
Cyclosporin A ◽  
Cell Injury ◽  
Mitochondrial Permeability Transition ◽  
Apoptotic Cell ◽  
Permeability Transition ◽  
Matrix Space ◽  
Necrosis Factor Alpha ◽  
Mitochondrial Permeability

Opening of a high-conductance pore in the mitochondrial inner membrane induces onset of the mitochondrial permeability transition (mPT). Cyclosporin A and trifluoperazine inhibit this pore and block necrotic cell death in oxidative stress, Ca2+ ionophore toxicity, Reye-related drug toxicity, pH-dependent ischaemia/reperfusion injury and other models of cell injury. Confocal fluorescence microscopy directly visualizes the increased mitochondrial membrane permeability of the mPT from the movement of calcein from the cytosol into the matrix space. Pyridine nucleotide oxidation, increased mitochondrial Ca2+ and mitochondrial generation of reactive oxygen species (ROS) all contribute to the onset of the mPT in situ. Confocal microscopy also shows directly that the mPT is a critical link in apoptotic signalling by tumour necrosis factor-alpha at a point downstream of caspase 8 and upstream of caspase 3. Cyclosporin A blocks this mPT, preventing release of pro-apoptotic cytochrome c from mitochondria and subsequent apoptotic cell killing. Progression to necrosis or apoptosis after the mPT depends on the availability of ATP, which blocks necrosis but promotes the apoptotic programme. Given the pathophysiological importance of the mPT, development of agents to modulate the mPT represents an important new goal for pharmaceutical drug discovery.

scholarly journals Cyclophilin D knockout protects the mouse kidney against cyclosporin A-induced oxidative stress

2019 ◽  
Vol 317 (3) ◽  
pp. F683-F694 ◽  
Author(s):  
Jelena Klawitter ◽  
Jost Klawitter ◽  
Alexander Pennington ◽  
Bruce Kirkpatrick ◽  
Galen Roda ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cyclosporin A ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mouse Kidney ◽  
Protective Effects ◽  
Cyclophilin D ◽  
Dna Hypomethylation ◽  
And Oxidative Stress

Mitochondrial dysfunction and oxidative stress have been implicated in cyclosporin A (CsA)-induced nephrotoxicity. CsA interacts with cyclophilin D (CypD), an essential component of the mitochondrial permeability transition pore and regulator of cell death processes. Controversial reports have suggested that CypD deletion may or may not protect cells against oxidative stress-induced cell death. In the present study, we treated wild-type (WT) mice and mice lacking CypD [peptidylprolyl isomerase F knockout ( Ppif−/−) mice] with CsA to test the role and contribution of CypD to the widely described CsA-induced renal toxicity and oxidative stress. Our results showed an increase in the levels of several known uremic toxins as well as the oxidative stress markers PGF2α and 8-isoprostane in CsA-treated WT animals but not in Ppif−/− animals. Similarly, a decline in S-adenosylmethionine and the resulting methylation potential indicative of DNA hypomethylation were observed only in CsA-treated WT mice. This confirms previous reports of the protective effects of CypD deletion on the mouse kidney mediated through a stronger resistance of these animals to oxidative stress and DNA methylation damage. However, a negative effect of CsA on the glycolysis and overall energy metabolism in Ppif−/− mice also indicated that additional, CypD-parallel pathways are involved in the toxic effects of CsA on the kidney. In summary, CsA-mediated induction of oxidative stress is associated with CypD, with CypD deletion providing a protective effect, whereas the reduction of energy production observed upon CsA exposure did not depend on the animals’ CypD status.

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