scholarly journals Cyclosporin A inhibits caspase-independent death of NGF-deprived sympathetic neurons

2002 ◽  
Vol 157 (5) ◽  
pp. 771-781 ◽  
Author(s):  
Louis K. Chang ◽  
Eugene M. Johnson
Keyword(s):  
Cell Death ◽  
Cyclosporin A ◽  
Apoptotic Cell ◽  
Sympathetic Neurons ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Critical Event ◽  
Nonapoptotic Cell Death

Opening of the permeability transition pore (PTP) has been implicated as an important mitochondrial event that occurs during apoptosis. We examined the role of the PTP in the well-characterized cell death of rat sympathetic neurons deprived of nerve growth factor (NGF) in vitro. Removal of NGF causes these neurons to undergo either a classic apoptotic cell death or, when treated with a broad-spectrum caspase inhibitor such as boc-aspartyl(OMe)-fluoromethylketone (BAF), a delayed, nonapoptotic cell death. The PTP inhibitor, cyclosporin A (CsA), blocked commitment-to-die in the presence of BAF, as defined by the ability of NGF readdition to rescue cells, but had little effect on commitment-to-die in the absence of BAF. CsA did not have trophic effects on BAF-saved cells, but did block the decrease in mitochondrial membrane potential. These data suggest that PTP opening is a critical event in caspase-independent, nonapoptotic (but not caspase-dependent, apoptotic) death of NGF-deprived rat sympathetic neurons.

scholarly journals JNK1/2 regulates ER–mitochondrial Ca2+ cross-talk during IL-1β–mediated cell death in RINm5F and human primary β-cells

2013 ◽  
Vol 24 (12) ◽  
pp. 2058-2071 ◽  
Author(s):  
Gaurav Verma ◽  
Himanshi Bhatia ◽  
Malabika Datta
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Mitochondrial Permeability Transition ◽  
Apoptotic Cell ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Β Cells ◽  
Mediating Role ◽  
Induced Apoptosis

Elevated interleukin-1β (IL-1β) induces apoptosis in pancreatic β-cells through endoplasmic reticulum (ER) stress induction and subsequent c-jun-N-terminal kinase 1/2 (JNK1/2) activation. In earlier work we showed that JNK1/2 activation is initiated before ER stress and apoptotic induction in response to IL-1β. However, the detailed regulatory mechanisms are not completely understood. Because the ER is the organelle responsible for Ca2+ handling and storage, here we examine the effects of IL-1β on cellular Ca2+ movement and mitochondrial dysfunction and evaluate the role of JNK1/2. Our results show that in RINm5F cells and human primary β-cells, IL-1β alters mitochondrial membrane potential, mitochondrial permeability transition pore opening, ATP content, and reactive oxygen species production and these alterations are preceded by ER Ca2+ release via IP3R channels and mitochondrial Ca2+ uptake. All these events are prevented by JNK1/2 small interfering RNA (siRNA), indicating the mediating role of JNK1/2 in IL-1β–induced cellular alteration. This is accompanied by IL-1β–induced apoptosis, which is prevented by JNK1/2 siRNA and the IP3R inhibitor xestospongin C. This suggests a regulatory role of JNK1/2 in modulating the ER-mitochondrial-Ca2+ axis by IL-1β in apoptotic cell death.

scholarly journals Alternating metabolic pathways in NGF-deprived sympathetic neurons affect caspase-independent death

2003 ◽  
Vol 162 (2) ◽  
pp. 245-256 ◽  
Author(s):  
Louis K. Chang ◽  
Robert E. Schmidt ◽  
Eugene M. Johnson
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Apoptotic Cell ◽  
Sympathetic Neurons ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Minor Role ◽  
Caspase Inhibitor ◽  
Cytochrome C Release ◽  
Independent Manner

Mitochondrial release of cytochrome c in apoptotic cells activates caspases, which execute apoptotic cell death. However, the events themselves that culminate in caspase activation can have deleterious effects because caspase inhibitor–saved cells ultimately die in a caspase-independent manner. To determine what events may underlie this form of cell death, we examined bioenergetic changes in sympathetic neurons deprived of NGF in the presence of a broad-spectrum caspase inhibitor, boc-aspartyl-(OMe)-fluoromethylketone. Here, we report that NGF-deprived, boc-aspartyl-(OMe)-fluoromethylketone–saved neurons rely heavily on glycolysis for ATP generation and for survival. Second, the activity of F0F1 contributes to caspase-independent death, but has only a minor role in the maintenance of mitochondrial membrane potential, which is maintained primarily by electron transport. Third, permeability transition pore inhibition by cyclosporin A attenuates NGF deprivation–induced loss of mitochondrial proteins, suggesting that permeability transition pore opening may have a function in regulating the degradation of mitochondria after cytochrome c release. Identification of changes in caspase inhibitor–saved cells may provide the basis for rational strategies to augment the effectiveness of the therapeutic use of postmitochondrial interventions.

A role for mitochondrial aquaporins in cellular life-and-death decisions?

2006 ◽  
Vol 291 (2) ◽  
pp. C195-C202 ◽  
Author(s):  
Wing-Kee Lee ◽  
Frank Thévenod
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Water Movement ◽  
Apoptotic Cell ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Inner Mitochondrial Membrane ◽  
Osmotic Swelling ◽  
Life And Death

Mitochondria dominate the process of life-and-death decisions of the cell. Continuous generation of ATP is essential for cell sustenance, but, on the other hand, mitochondria play a central role in the orchestra of events that lead to apoptotic cell death. Changes of mitochondrial volume contribute to the modulation of physiological mitochondrial function, and several ion permeability pathways located in the inner mitochondrial membrane have been implicated in the mediation of physiological swelling-contraction reactions, such as the K+ cycle. However, the channels and transporters involved in these processes have not yet been identified. Osmotic swelling is also one of the fundamental characteristics exhibited by mitochondria in pathological situations, which activates downstream cascades, culminating in apoptosis. The permeability transition pore has long been postulated to be the primary mediator for water movement in mitochondrial swelling during cell death, but its molecular identity remains obscure. Inevitably, accumulating evidence shows that mitochondrial swelling induced by apoptotic stimuli can also occur independently of permeability transition pore activation. Recently, a novel mechanism for osmotic swelling of mitochondria has been described. Aquaporin-8 and -9 channels have been identified in the inner mitochondrial membrane of various tissues, including the kidney, liver, and brain, where they may mediate water transport associated with physiological volume changes, contribute to the transport of metabolic substrates, and/or participate in osmotic swelling induced by apoptotic stimuli. Hence, the recent discovery that aquaporins are expressed in mitochondria opens up new areas of investigation in health and disease.

scholarly journals Cell Death and Ageing – A Question of Cell Type

2002 ◽  
Vol 2 ◽  
pp. 943-948 ◽  
Author(s):  
Pidder Jansen-Dürr
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Replicative Senescence ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Ageing Process ◽  
Human Ageing

Replicative senescence of human cells in primary culture is a widely accepted model for studying the molecular mechanisms of human ageing. The standard model used for studying human ageing consists of fibroblasts explanted from the skin and grown intoin vitrosenescence. From this model, we have learned much about molecular mechanisms underlying the human ageing process; however, the model presents clear limitations. In particular, a long-standing dogma holds that replicative senescence involves resistance to apoptosis, a belief that has led to considerable confusion concerning the role of apoptosis during human ageing. While there are data suggesting that apoptotic cell death plays a key role for ageingin vitroand in the pathogenesis of various age-associated diseases, this is not reflected in the current literature onin vitrosenescence. In this article, I summarize key findings concerning the relationship between apoptosis and ageingin vivoand also review the literature concerning the role of apoptosis during in vitro senescence. Recent experimental findings, summarized in this article, suggest that apoptotic cell death (and probably other forms of cell death) are important features of the ageing process that can also be recapitulated in tissue culture systems to some extent. Another important lesson to learn from these studies is that mechanisms ofin vivosenescence differ considerably between various histotypes.

scholarly journals HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart

2015 ◽  
Vol 112 (47) ◽  
pp. E6466-E6475 ◽  
Author(s):  
Chi Keung Lam ◽  
Wen Zhao ◽  
Guan-Sheng Liu ◽  
Wen-Feng Cai ◽  
George Gardner ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Membrane ◽  
Human Lymphocytes ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Membrane Function ◽  
Genetic Ablation

The major underpinning of massive cell death associated with myocardial infarction involves opening of the mitochondrial permeability transition pore (mPTP), resulting in disruption of mitochondria membrane integrity and programmed necrosis. Studies in human lymphocytes suggested that the hematopoietic-substrate-1 associated protein X-1 (HAX-1) is linked to regulation of mitochondrial membrane function, but its role in controlling mPTP activity remains obscure. Herein we used models with altered HAX-1 expression levels in the heart and uncovered an unexpected role of HAX-1 in regulation of mPTP and cardiomyocyte survival. Cardiac-specific HAX-1 overexpression was associated with resistance against loss of mitochondrial membrane potential, induced by oxidative stress, whereas HAX-1 heterozygous deficiency exacerbated vulnerability. The protective effects of HAX-1 were attributed to specific down-regulation of cyclophilin-D levels leading to reduction in mPTP activation. Accordingly, cyclophilin-D and mPTP were increased in heterozygous hearts, but genetic ablation of cyclophilin-D in these hearts significantly alleviated their susceptibility to ischemia/reperfusion injury. Mechanistically, alterations in cyclophilin-D levels by HAX-1 were contributed by the ubiquitin-proteosomal degradation pathway. HAX-1 overexpression enhanced cyclophilin-D ubiquitination, whereas proteosomal inhibition restored cyclophilin-D levels. The regulatory effects of HAX-1 were mediated through interference of cyclophilin-D binding to heat shock protein-90 (Hsp90) in mitochondria, rendering it susceptible to degradation. Accordingly, enhanced Hsp90 expression in HAX-1 overexpressing cardiomyocytes increased cyclophilin-D levels, as well as mPTP activation upon oxidative stress. Taken together, our findings reveal the role of HAX-1 in regulating cyclophilin-D levels via an Hsp90-dependent mechanism, resulting in protection against activation of mPTP and subsequent cell death responses.

scholarly journals The Permeability Transition Pore Complex: A Target for Apoptosis Regulation by Caspases and Bcl-2–related Proteins

1998 ◽  
Vol 187 (8) ◽  
pp. 1261-1271 ◽  
Author(s):  
Isabel Marzo ◽  
Catherine Brenner ◽  
Naoufal Zamzami ◽  
Santos A. Susin ◽  
Gisela Beutner ◽  
...  
Keyword(s):  
Cell Death ◽  
Cyclosporin A ◽  
Adenine Nucleotide ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Functional Behavior ◽  
Massive Cell Death ◽  
Pore Complexes ◽  
Apoptosis Regulation

Early in programmed cell death (apoptosis), mitochondrial membrane permeability increases. This is at least in part due to opening of the permeability transition (PT) pore, a multiprotein complex built up at the contact site between the inner and the outer mitochondrial membranes. The PT pore has been previously implicated in clinically relevant massive cell death induced by toxins, anoxia, reactive oxygen species, and calcium overload. Here we show that PT pore complexes reconstituted in liposomes exhibit a functional behavior comparable with that of the natural PT pore present in intact mitochondria. The PT pore complex is regulated by thiol-reactive agents, calcium, cyclophilin D ligands (cyclosporin A and a nonimmunosuppressive cyclosporin A derivative), ligands of the adenine nucleotide translocator, apoptosis-related endoproteases (caspases), and Bcl-2–like proteins. Although calcium, prooxidants, and several recombinant caspases (caspases 1, 2, 3, 4, and 6) enhance the permeability of PT pore-containing liposomes, recombinant Bcl-2 or Bcl-XL augment the resistance of the reconstituted PT pore complex to pore opening. Mutated Bcl-2 proteins that have lost their cytoprotective potential also lose their PT modulatory capacity. In conclusion, the PT pore complex may constitute a crossroad of apoptosis regulation by caspases and members of the Bcl-2 family.

scholarly journals OXPHOS Promotes Apoptotic Resistance and Persistence in TH17 cells

2021 ◽  
Author(s):  
Hanna S. Hong ◽  
Nneka E. Mbah ◽  
Mengrou Shan ◽  
Kristen Loesel ◽  
Lin Lin ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Cell Fate ◽  
Apoptotic Cell ◽  
Metabolic Phenotype ◽  
Tumor Studies ◽  
A Cell

AbstractApoptotic cell death is a cell-intrinsic, immune tolerance mechanism that regulates the magnitude and resolution of T cell-mediated responses. Evasion of apoptosis is critical for the generation of memory T cells, as well as autoimmune T cells, and knowledge of the mechanisms that enable resistance to apoptosis will provide insight into ways to modulate their activity during protective and pathogenic responses. IL-17-producing CD4 T cells (TH17s) are long-lived, memory cells. These features enable their role in host defense, chronic inflammatory disorders, and anti-tumor immunity. A growing number of reports now indicate that TH17s in vivo require mitochondrial oxidative phosphorylation (OXPHOS), a metabolic phenotype that is poorly induced in vitro. To elucidate the role of OXPHOS in TH17 processes, we developed a system to polarize TH17s that metabolically resembled their in vivo counterparts. We discovered that directing TH17s to use OXPHOS promotes mitochondrial fitness, glutamine anaplerosis, and an anti-apoptotic phenotype marked by high BCL-XL and low BIM. Through competitive co-transfer experiments and tumor studies, we further revealed how OXPHOS protects TH17s from cell death while enhancing their persistence in the periphery and tumor microenvironment. Together, our work demonstrates a non-classical role of metabolism in regulating TH17 cell fate and highlights the potential for therapies that target OXPHOS in TH17-driven diseases.

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.

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