scholarly journals Puma, a critical mediator of cell death — one decade on from its discovery

2012 ◽  
Vol 17 (4) ◽  
Author(s):  
Paweł Hikisz ◽  
Zofia Kiliańska
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Membrane ◽  
Viral Infections ◽  
Outer Mitochondrial Membrane ◽  
Caspase Activation ◽  
Bh3 Domain ◽  
Puma Gene ◽  
Induction Of Apoptosis

AbstractPUMA (p53 upregulated modulator of apoptosis) is a pro-apoptotic member of the BH3-only subgroup of the Bcl-2 family. It is a key mediator of p53-dependent and p53-independent apoptosis and was identified 10 years ago. The PUMA gene is mapped to the long arm of chromosome 19, a region that is frequently deleted in a large number of human cancers. PUMA mediates apoptosis thanks to its ability to directly bind known anti-apoptotic members of the Bcl-2 family. It mainly localizes to the mitochondria. The binding of PUMA to the inhibitory members of the Bcl-2 family (Bcl-2-like proteins) via its BH3 domain seems to be a critical regulatory step in the induction of apoptosis. It results in the displacement of the proteins Bax and/or Bak. This is followed by their activation and the formation of pore-like structures on the mitochondrial membrane, which permeabilizes the outer mitochondrial membrane, leading to mitochondrial dysfunction and caspase activation. PUMA is involved in a large number of physiological and pathological processes, including the immune response, cancer, neurodegenerative diseases and bacterial and viral infections.

Bcl-2 Family of Proteins: Life-or-Death Switch in Mitochondria

2002 ◽  
Vol 22 (1) ◽  
pp. 47-58 ◽  
Author(s):  
Yoshihide Tsujimoto
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Apoptotic Cell ◽  
Regulatory Protein ◽  
Family Members ◽  
Anion Channel ◽  
Permeability Transition ◽  
Outer Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
Membrane Barrier

An increase in the permeability of outer mitochondrial membrane is central to apoptotic cell death, and results in the release of several apoptogenic factors such as cytochrome c into the cytoplasm to activate downstream destructive programs. The voltage-dependent anion channel (VDAC or mitochondrial porin) plays an essential role in disrupting the mitochondrial membrane barrier and is regulated directly by members of the Bcl-2 family proteins. Anti-apoptotic Bcl-2 family members interact with and close the VDAC, whereas some, but not all, proapoptotic members interact with VDAC to open protein-conducting pore through which apoptogenic factors pass. Although the VDAC is involved directly in breaking the mitochondrial membrane barrier and is a known component of the permeability transition pore complex, VDAC-dependent increase in outer membrane permeability can be independent of the permeability transition event such as mitochondrial swelling followed by rupture of the outer mitochondrial membrane. VDAC interacts not only with Bcl-2 family members but also with proteins such as gelsolin, an actin regulatory protein, and appears to be a convergence point for a variety of cell survival and cell death signals.

Vitamin E prevents hypobaric hypoxia-induced mitochondrial dysfunction in skeletal muscle

2007 ◽  
Vol 113 (12) ◽  
pp. 459-466 ◽  
Author(s):  
José Magalhães ◽  
Rita Ferreira ◽  
Maria J. Neuparth ◽  
Paulo J. Oliveira ◽  
Franklim Marques ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Vitamin E ◽  
Mitochondrial Dysfunction ◽  
Hypobaric Hypoxia ◽  
Mitochondrial Membrane ◽  
Mitochondrial Protein ◽  
Membrane Integrity ◽  
Outer Mitochondrial Membrane ◽  
Hypoxia Exposure

In the present study, the effect of vitamin E (α-tocopherol) on mice skeletal muscle mitochondrial dysfunction and oxidative damage induced by an in vivo acute and severe hypobaric hypoxic insult (48 h at a barometric pressure equivalent to 8500 m) has been investigated. Male mice (n=24) were randomly divided into the following four groups (n=6): control (C), hypoxia (H), vitamin E (VE; 60 mg/kg of body weight intraperitoneally, three times/week for 3 weeks) and hypoxia+VE (HVE). A significant increase in mitochondrial protein CGs (carbonyl groups) was found in the H group compared with the C group. Confirming previous observations from our group, hypoxia induced mitochondrial dysfunction, as identified by altered respiratory parameters. Hypoxia exposure increased Bax content and decreased the Bcl-2/Bax ratio, whereas Bcl-2 remained unchanged. Inner and outer mitochondrial membrane integrity were significantly affected by hypoxia exposure; however, vitamin E treatment attenuated the effect of hypoxia on mitochondrial oxidative phosphorylation and on the levels of CGs. Vitamin E supplementation also prevented the Bax and Bcl-2/Bax ratio impairments caused by hypoxia, as well as the decrease in inner and outer mitochondrial membrane integrity. In conclusion, the results suggest that vitamin E prevents the loss of mitochondrial integrity and function, as well as the increase in Bax content, which suggests that mitochondria are involved in increased cell death induced by severe hypobaric hypoxia in mice skeletal muscle.

scholarly journals Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Briana R. De Miranda ◽  
Emily M. Rocha ◽  
Sandra L. Castro ◽  
J. Timothy Greenamyre
Keyword(s):  
Substantia Nigra ◽  
Mitochondrial Dysfunction ◽  
Dopaminergic Neurons ◽  
Mitochondrial Membrane ◽  
Expression System ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Import ◽  
In Vivo Models ◽  
Dopaminergic Neurodegeneration ◽  
Import Receptor

AbstractDopaminergic neurons of the substantia nigra are selectively vulnerable to mitochondrial dysfunction, which is hypothesized to be an early and fundamental pathogenic mechanism in Parkinson’s disease (PD). Mitochondrial function depends on the successful import of nuclear-encoded proteins, many of which are transported through the TOM20–TOM22 outer mitochondrial membrane import receptor machinery. Recent data suggests that post-translational modifications of α-synuclein promote its interaction with TOM20 at the outer mitochondrial membrane and thereby inhibit normal protein import, leading to dysfunction, and death of dopaminergic neurons. As such, preservation of mitochondrial import in the face of α-synuclein accumulation might be a strategy to prevent dopaminergic neurodegeneration, however, this is difficult to assess using current in vivo models of PD. To this end, we established an exogenous co-expression system, utilizing AAV2 vectors to overexpress human α-synuclein and TOM20, individually or together, in the adult Lewis rat substantia nigra to assess whether TOM20 overexpression attenuates α-synuclein-induced dopaminergic neurodegeneration. Twelve weeks after viral injection, we observed that AAV2-TOM20 expression was sufficient to prevent loss of nigral dopaminergic neurons caused by AAV2-αSyn overexpression. The observed TOM20-mediated dopaminergic neuron preservation appeared to be due, in part, to the rescued expression (and presumed import) of nuclear-encoded mitochondrial electron transport chain proteins that were inhibited by α-synuclein overexpression. In addition, TOM20 overexpression rescued the expression of the chaperone protein GRP75/mtHSP70/mortalin, a stress-response protein involved in α-synuclein-induced injury. Collectively, these data indicate that TOM20 expression prevents α-synuclein-induced mitochondrial dysfunction, which is sufficient to rescue dopaminergic neurons in the adult rat brain.

Death by association: BH3 domain-only proteins and liver injury

2005 ◽  
Vol 289 (6) ◽  
pp. G987-G990 ◽  
Author(s):  
E. S. Baskin-Bey ◽  
G. J. Gores
Keyword(s):  
Cell Death ◽  
Liver Injury ◽  
Mitochondrial Dysfunction ◽  
Liver Cell ◽  
Liver Diseases ◽  
Chronic Liver Diseases ◽  
Concise Review ◽  
Bh3 Domain ◽  
A Cell

Apoptosis, a prominent form of cell death, is a prime feature of many acute and chronic liver diseases. Apoptosis requires mitochondrial dysfunction, which is regulated by proteins of the Bcl-2 family. Whether or not a cell should live or die is controlled by the interaction of multidomain Bcl-2 proteins with proapoptotic BH3 domain-only proteins of this family. Current models suggest multidomain, antiapoptotic Bcl-2 proteins prevent mitochondrial dysfunction by sequestering and/or preventing activation of its proapoptotic relatives. BH3-only proteins initiate cell death by neutralizing and or ligating multidomain prosurvival Bcl-2 proteins. Thus BH3 domain-only proteins are paramount in the apoptotic process as exemplified by the role of the BH3 domain-only protein Bid in liver injury. In this concise review, we will focus on how these BH3 domain-only proteins are regulated in the cell, their association with the Bcl-2 family of proteins, and finally, current information regarding their involvement in liver cell apoptosis and injury.

scholarly journals Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak

2021 ◽  
Vol 9 ◽  
Author(s):  
Pooja Patel ◽  
Arielys Mendoza ◽  
Dexter J. Robichaux ◽  
Meng C. Wang ◽  
Xander H. T. Wehrens ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Family Member ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Inner Mitochondrial Membrane ◽  
Retention Capacity

Mitochondrial permeability transition pore (MPTP)-dependent necrosis contributes to numerous pathologies in the heart, brain, and skeletal muscle. The MPTP is a non-selective pore in the inner mitochondrial membrane that is triggered by high levels of matrix Ca2+, and sustained opening leads to mitochondrial dysfunction. Although the MPTP is defined by an increase in inner mitochondrial membrane permeability, the expression of pro-apoptotic Bcl-2 family members, Bax and Bak localization to the outer mitochondrial membrane is required for MPTP-dependent mitochondrial dysfunction and subsequent necrotic cell death. Contrary to the role of Bax and Bak in apoptosis, which is dependent on their oligomerization, MPTP-dependent necrosis does not require oligomerization as monomeric/inactive forms of Bax and Bak can facilitate mitochondrial dysfunction. However, the relationship between Bax and Bak activation/oligomerization and MPTP sensitization remains to be explored. Here, we use a combination of in vitro and ex vivo approaches to determine the role of the anti-apoptotic Bcl-2 family members, which regulate Bax/Bak activity, in necrotic cell death and MPTP sensitivity. To study the role of each predominantly expressed anti-apoptotic Bcl-2 family member (i.e., Mcl-1, Bcl-2, and Bcl-xL) in MPTP regulation, we utilize various BH3 mimetics that specifically bind to and inhibit each. We determined that the inhibition of each anti-apoptotic Bcl-2 family member lowers mitochondrial calcium retention capacity and sensitizes MPTP opening. Furthermore, the inhibition of each Bcl-2 family member exacerbates both apoptotic and necrotic cell death in vitro in a Bax/Bak-dependent manner. Our findings suggests that mitochondrial Ca2+ retention capacity and MPTP sensitivity is influenced by Bax/Bak activation/oligomerization on the outer mitochondrial membrane, providing further evidence of the crosstalk between the apoptotic and necrotic cell death pathways.

scholarly journals SARS-CoV-2 induces inflammasome-dependent pyroptosis and downmodulation of HLA-DR in human monocytes

2020 ◽  
Author(s):  
André C. Ferreira ◽  
Vinicius Cardoso Soares ◽  
Isaclaudia G. de Azevedo-Quintanilha ◽  
Suelen da Silva Gomes Dias ◽  
Natalia Fintelman-Rodrigues ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Severe Acute Respiratory Syndrome ◽  
Inflammatory Response ◽  
Inflammatory Cell ◽  
Viral Infections ◽  
Relevant Information ◽  
Inflammasome Activation ◽  
Human Monocytes ◽  
Hla Dr

AbstractInfection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with leukopenia and uncontrolled inflammatory response in critically ill patients. A better comprehension of SARS-CoV-2-induced monocyte death is essential for the identification of therapies capable to control the hyper-inflammation and reduce viral replication in patients with COVID-19. Here, we show that SARS-CoV-2 induces inflammasome activation and cell death by pyroptosis in human monocytes, experimentally infected and from patients under intensive care. Pyroptosis was dependent on caspase-1 engagement, prior to IL-1ß production and inflammatory cell death. Monocytes exposed to SARS-CoV-2 downregulate HLA-DR, suggesting a potential limitation to orchestrate the immune response. Our results originally describe mechanisms by which monocytes, a central cellular component recruited from peripheral blood to respiratory tract, succumb to control severe 2019 coronavirus disease (COVID-19).Author summarySince its emergence in China in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused thousands of deaths worldwide. Currently, the number of individuals infected with SARS-CoV-2 and in need of antiviral, anti-inflammatory, anticoagulant and more invasive treatments has overwhelmed the health systems worldwide. In our study, we found that SARS-CoV-2 is capable of inducing inflammatory cell death in human monocytes, one of the main cell types responsible for anti-SARS-CoV-2 immune response. As a consequence of this intracellular inflammatory mechanism (inflammasome engagement), an exacerbated production of inflammatory mediators occurs. The infection also decreases the expression of HLA-DR in monocytes, a molecule related to the orchestration of the immune response in case of viral infections. We also demonstrated that the HIV-1 protease inhibitor, atazanavir (ATV), prevented the uncontrolled inflammatory response, cell death and reduction in HLA-DR expression in SARS-CoV-2-infected monocytes. Our study provides relevant information on the effects of SARS-CoV-2 infection on human monocytes, as well as on the effect of ATV in preventing these pathological effects on the host.

Apoptosis: bombarding the mitochondria

2003 ◽  
Vol 39 ◽  
pp. 41-51 ◽  
Author(s):  
Philippe Parone ◽  
Muriel Priault ◽  
Dominic James ◽  
Steven F Nothwehr ◽  
Jean-Claude Martinou
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Membrane ◽  
Family Members ◽  
Reactive Oxygen ◽  
Intermembrane Space ◽  
Oxygen Species ◽  
Outer Mitochondrial Membrane ◽  
Caspase Activation ◽  
Mitochondrial Intermembrane Space ◽  
Death Signals

Mitochondria play a central role in apoptosis triggered by many stimuli. They integrate death signals through Bcl-2 family members and co-ordinate caspase activation through the release of apoptogenic factors that are normally sequestered in the mitochondrial intermembrane space. The release of these proteins is the result of the outer mitochondrial membrane becoming permeable. In addition, mitochondria can initiate apoptosis through the production of reactive oxygen species.

scholarly journals Bax and Bak Coalesce into Novel Mitochondria-Associated Clusters during Apoptosis

2001 ◽  
Vol 153 (6) ◽  
pp. 1265-1276 ◽  
Author(s):  
Amotz Nechushtan ◽  
Carolyn L. Smith ◽  
Itschak Lamensdorf ◽  
Soo-Han Yoon ◽  
Richard J. Youle
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Cluster Formation ◽  
Family Members ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Membranes ◽  
Mitochondrial Translocation ◽  
Novel Structure ◽  
Large Clusters ◽  
Confocal And Electron Microscopy

Bax is a member of the Bcl-2 family of proteins known to regulate mitochondria-dependent programmed cell death. Early in apoptosis, Bax translocates from the cytosol to the mitochondrial membrane. We have identified by confocal and electron microscopy a novel step in the Bax proapoptotic mechanism immediately subsequent to mitochondrial translocation. Bax leaves the mitochondrial membranes and coalesces into large clusters containing thousands of Bax molecules that remain adjacent to mitochondria. Bak, a close homologue of Bax, colocalizes in these apoptotic clusters in contrast to other family members, Bid and Bad, which circumscribe the outer mitochondrial membrane throughout cell death progression. We found the formation of Bax and Bak apoptotic clusters to be caspase independent and inhibited completely and specifically by Bcl-XL, correlating cluster formation with cytotoxic activity. Our results reveal the importance of a novel structure formed by certain Bcl-2 family members during the process of cell death.

Bax translocates from cytosol to mitochondria in cardiac cells during apoptosis: development of a GFP-Bax-stable H9c2 cell line for apoptosis analysis

2005 ◽  
Vol 289 (1) ◽  
pp. H477-H487 ◽  
Author(s):  
Qi Hou ◽  
Yi-Te Hsu
Keyword(s):  
Cell Death ◽  
Membrane Potential ◽  
Cell Line ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
H9c2 Cell ◽  
Serum Withdrawal ◽  
Induction Of Apoptosis ◽  
H9c2 Cell Line ◽  
Hypoxia Reoxygenation

The proapoptotic protein Bax plays an important role in cardiomyocytic cell death. Ablation of this protein has been shown to diminish cardiac damage in Bax-knockout mice during ischemia-reperfusion. Presently, studies of Bax-mediated cardiac cell death examined primarily the expression levels of Bax and its prosurvival factor Bcl-2 rather than the localization of this protein, which dictates its function. Using immunofluorescence labeling, we have shown that in neonatal rat cardiomyocytes and in H9c2 cardiomyoblasts, Bax translocates from cytosol to mitochondria upon the induction of apoptosis by hypoxia-reoxygenation-serum withdrawal and by the presence of the free-radical inducer menadione. Also, we found that Bax translocation to mitochondria was associated with the exposure of an NH2-terminal epitope, and that this translocation could be partially blocked by the prosurvival factors Bcl-2 and Bcl-XL. To visualize the translocation of Bax in living cells, we have developed an H9c2 cell line that stably expresses green fluorescent protein (GFP)-tagged Bax. This cell line has GFP-Bax localized primarily in the cytosol in the absence of apoptotic inducers. Upon induction of apoptosis by a number of stimuli, including menadione, staurosporine, sodium nitroprusside, and hypoxia-reoxygenation-serum withdrawal, we could observe the translocation of Bax from cytosol to mitochondria. This translocation was not affected by retinoic acid-induced differentiation of H9c2 cells. Additionally, this translocation was associated with loss of mitochondrial membrane potential, release of cytochrome c, and fragmentation of nuclei. Finally, using a tetramethylrhodamine-based dye, we have shown that a rapid screening process based on the loss of mitochondrial membrane potential could be developed to monitor GFP-Bax translocation to mitochondria. Overall, the GFP-Bax-stable H9c2 cell line that we have developed represents a unique tool for examining Bax-mediated apoptosis, and it could be of great importance in screening therapeutic compounds that could block Bax translocation to mitochondria to attenuate apoptosis.

scholarly journals The study of cell-death proteins in the outer mitochondrial membrane by chemical cross-linking

1997 ◽  
Vol 325 (2) ◽  
pp. 321-324 ◽  
Author(s):  
Sohail T. ALI ◽  
John R. COGGINS ◽  
Howard T. JACOBS
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Mitochondrial Protein ◽  
Surface Proteins ◽  
Cross Linking ◽  
Outer Mitochondrial Membrane ◽  
Cross Link ◽  
Cell Death Protein ◽  
Chemical Cross Linking

Chemical cross-linking was used to study the interactions of the anti-cell-death protein Bcl2 with other proteins in the outer mitochondrial membrane. Cross-linking of mitochondrial surface proteins produced a large Bcl2-containing complex (> 200 kDa), and a Bcl2-derived peptide was shown to cross-link specifically with a mitochondrial protein identified by immunoblotting as Raf-1 kinase.

Sign in / Sign up

Export Citation Format

Share Document