scholarly journals Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways

2011 ◽  
Vol 300 (1) ◽  
pp. H118-H124 ◽  
Author(s):  
Ethan J. Anderson ◽  
Evelio Rodriguez ◽  
Curtis A. Anderson ◽  
Kathleen Thayne ◽  
W. Randolph Chitwood ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Coronary Revascularization ◽  
Diabetic Patients ◽  
Extrinsic Pathway ◽  
Apoptosis Pathway ◽  
Atrial Tissue ◽  
Intrinsic Apoptosis Pathway

Progressive energy deficiency and loss of cardiomyocyte numbers are two prominent factors that lead to heart failure in experimental models. Signals that mediate cardiomyocyte cell death have been suggested to come from both extrinsic (e.g., cytokines) and intrinsic (e.g., mitochondria) sources, but the evidence supporting these mechanisms remains unclear, and virtually nonexistent in humans. In this study, we investigated the sensitivity of the mitochondrial permeability transition pore (mPTP) to calcium (Ca2+) using permeabilized myofibers of right atrium obtained from diabetic ( n = 9) and nondiabetic ( n = 12) patients with coronary artery disease undergoing nonemergent coronary revascularization surgery. Under conditions that mimic the energetic state of the heart in vivo (pyruvate, glutamate, malate, and 100 μM ADP), cardiac mitochondria from diabetic patients show an increased sensitivity to Ca2+-induced mPTP opening compared with nondiabetic patients. This increased mPTP Ca2+ sensitivity in diabetic heart mitochondria is accompanied by a substantially greater rate of mitochondrial H2O2 emission under identical conditions, despite no differences in respiratory capacity under these conditions or mitochondrial enzyme content. Activity of the intrinsic apoptosis pathway mediator caspase-9 was greater in diabetic atrial tissue, whereas activity of the extrinsic pathway mediator caspase-8 was unchanged between groups. Furthermore, caspase-3 activity was not significantly increased in diabetic atrial tissue. These data collectively suggest that the myocardium in diabetic patients has a greater overall propensity for mitochondrial-dependent cell death, possibly as a result of metabolic stress-imposed changes that have occurred within the mitochondria, rendering them more susceptible to insults such as Ca2+ overload. In addition, they lend further support to the notion that mitochondria represent a viable target for future therapies directed at ameliorating heart failure and other comorbidities that come with diabetes.

Platelet Death.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-40-sci-40
Author(s):  
Emma C. Josefsson ◽  
Simone Schoenwaelder ◽  
Michael White ◽  
Matthew Goschnick ◽  
Andrew W. Roberts ◽  
...  
Keyword(s):  
Cell Death ◽  
Cultured Cells ◽  
Preliminary Evidence ◽  
Human Platelets ◽  
Mitochondrial Damage ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Abstract Human platelets exhibit a circulating lifespan of ~10 days, mouse platelets ~5 days. This finite existence is circumscribed by members of the Bcl-2 family of proteins, which control the intrinsic apoptosis pathway. Pro-survival Bcl-xL is the critical regulator of platelet lifespan, functioning to keep pro-death Bak and Bax in check, thereby maintaining platelet viability. After 5–10 days in the circulation, platelets not consumed in hemostatic processes initiate a Bak and Bax-dependent cell death program and clearance from the bloodstream. Mutations in Bcl-xL reduce platelet lifespan in a dose-dependent fashion, while deletion of Bak and Bax extend it. Studies with the BH3 mimetic compound ABT-737, which inhibits pro-survival Bcl-xL, have shown that platelets induced to undergo cell death in vitro exhibit many of the hallmarks of apoptosis in nucleated cells, including mitochondrial damage, caspase activation and externalization of membrane phosphatidylserine (PS). Whether any of these features occur during physiological platelet clearance remains unclear. Certainly, mitochondrial damage can reduce the recovery of transfused platelets, but whether PS – which is known to promote the pro-coagulant activity of agonist-activated platelets – also acts as a clearance signal for dying platelets in vivo is yet to be established. Conversely, Bak and Bax may play a role in mediating PS exposure triggered by activation. Supporting the idea that there may be crosstalk between classical platelet signaling pathways and the intrinsic apoptosis pathway is recent evidence that platelet agonists can also activate caspases. Intriguingly, elements of the intrinsic pathway may also contribute to the generation of platelets by megakaryocytes. Several groups have demonstrated that megakaryocytes contain activated caspases and that their inhibition can block platelet shedding by cultured cells. Preliminary evidence we have generated suggests that Bcl-2 family proteins may be required for platelet production in vivo. Thus, it appears that there is much to be understood about the role of the intrinsic apoptosis pathway in the regulation of platelet biogenesis, function, and death.

scholarly journals The role of BH3-only proteins in apoptosis within the ovary

Reproduction ◽  
2015 ◽  
Vol 149 (2) ◽  
pp. R81-R89 ◽  
Author(s):  
Karla J Hutt
Keyword(s):  
Cell Death ◽  
Endocrine Function ◽  
Environmental Toxicants ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Bcl2 Family ◽  
Intrinsic Apoptosis Pathway

BH3-only proteins are pro-apoptotic members of the BCL2 family that play pivotal roles in embryonic development, tissue homeostasis and immunity by triggering cell death through the intrinsic apoptosis pathway. Recentin vitroandin vivostudies have demonstrated that BH3-only proteins are also essential mediators of apoptosis within the ovary and are responsible for the initiation of the cell death signalling cascade in a cell type and stimulus-specific fashion. This review gives a brief overview of the intrinsic apoptosis pathway and summarise the roles of individual BH3-only proteins in the promotion of apoptosis in embryonic germ cells, oocytes, follicular granulosa cells and luteal cells. The role of these proteins in activating apoptosis in response to developmental cues and cell stressors, such as exposure to chemotherapy, radiation and environmental toxicants, is described. Studies on the function of BH3-only proteins in the ovary are providing valuable insights into the regulation of oocyte number and quality, as well as ovarian endocrine function, which collectively influence the female reproductive lifespan and health.

scholarly journals Mitochondrial fission process 1 (MTFP1) controls bioenergetic efficiency and prevents inflammatory cardiomyopathy and heart failure in mice

2021 ◽  
Author(s):  
Erminia Donnarumma ◽  
Michael Kohlhaas ◽  
Elodie Vimont ◽  
Etienne Kornobis ◽  
Thibaut Chaze ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cell Death ◽  
Knockout Mice ◽  
Mitochondrial Permeability Transition ◽  
Mitochondrial Fission ◽  
Sterile Inflammation ◽  
Mitochondrial Morphology ◽  
Fission Process ◽  
General Decline

Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in adult-onset dilated cardiomyopathy (DCM) characterized by sterile inflammation and cardiac fibrosis that progressed to heart failure and middle-aged death. Failing hearts from cardiomyocyte-restricted knockout mice displayed a general decline in mitochondrial gene expression and oxidative phosphorylation (OXPHOS) activity. Pre-DCM, we observed no defects in mitochondrial morphology, content, gene expression, OXPHOS assembly nor phosphorylation dependent respiration. However, knockout cardiac mitochondria displayed reduced membrane potential and increased non-phosphorylation dependent respiration, which could be rescued by pharmacological inhibition of the adenine nucleotide translocase ANT. Primary cardiomyocytes from pre-symptomatic knockout mice exhibited normal excitation-contraction coupling but increased sensitivity to programmed cell death (PCD), which was accompanied by an opening of the mitochondrial permeability transition pore (mPTP). Intriguingly, mouse embryonic fibroblasts deleted for Mtfp1 recapitulated PCD sensitivity and mPTP opening, both of which could be rescued by pharmacological or genetic inhibition of the mPTP regulator Cyclophilin D. Collectively, our data demonstrate that contrary to previous in vitro studies, the loss of the MTFP1 promotes mitochondrial uncoupling and increases cell death sensitivity, causally mediating pathogenic cardiac remodeling.

scholarly journals Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and the Bcl-2 Protein Family

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Christopher Platen ◽  
Stephan Dreschers ◽  
Jessica Wappler ◽  
Andreas Ludwig ◽  
Stefan Düsterhöft ◽  
...  
Keyword(s):  
Cell Death ◽  
Bacterial Infections ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Intrinsic Apoptosis ◽  
Caspase 9 ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Neonates are extremely susceptible to bacterial infections, and evidences suggest that phagocytosis-induced cell death (PICD) is less frequently triggered in neonatal monocytes than in monocytes from adult donors. An insufficient termination of the inflammatory response, leading to a prolonged survival of neonatal monocytes with ongoing proinflammatory cytokine release, could be associated with the progression of various inflammatory diseases in neonates. Our previous data indicate that amphiregulin (AREG) is increasingly expressed on the cell surface of neonatal monocytes, resulting in remarkably higher soluble AREG levels after proteolytic shedding. In this study, we found that E. coli-infected neonatal monocytes show an increased phosphorylation of ERK, increased expression of Bcl-2 and Bcl-XL, and reduced levels of cleaved caspase-3 and caspase-9 compared to adult monocytes. In both cell types, additional stimulation with soluble AREG further increased ERK activation and expression of Bcl-2 and Bcl-XL and reduced levels of cleaved caspase-3 and caspase-9 in an EGFR-dependent manner. These data suggest that reduced PICD of neonatal monocytes could be due to reduced intrinsic apoptosis and that AREG can promote protection against PICD. This reduction of the intrinsic apoptosis pathway in neonatal monocytes could be relevant for severely prolonged inflammatory responses of neonates.

scholarly journals Cell death following the loss of ADAR1 mediated A-to-I RNA editing is not effected by the intrinsic apoptosis pathway

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Carl R. Walkley ◽  
Benjamin T. Kile
Keyword(s):  
Cell Death ◽  
Rna Editing ◽  
Rna Structure ◽  
Fetal Liver ◽  
Loss Of Function ◽  
Intrinsic Apoptosis ◽  
Triple Mutant ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

AbstractModifications of RNA, collectively termed as the epitranscriptome, are widespread, evolutionarily conserved and contribute to gene regulation and protein diversity in healthy and disease states. There are >160 RNA modifications described, greatly exceeding the number of modifications to DNA. Of these, adenosine-to-inosine (A-to-I) RNA editing is one of the most common. There are tens of thousands of A-to-I editing sites in mouse, and millions in humans. Upon translation or sequencing an inosine base is decoded as guanosine, leading to A-to-G mismatches between the RNA and DNA. Inosine has different base pairing properties to adenosine and as a result editing not only alters the RNA code but can also change the RNA structure. In mammals A-to-I editing is performed by ADAR1 and ADAR2. A feature of murine loss of function ADAR1 alleles is cell death and a failure to survive embryogenesis. Adar1−/− and editing deficient (Adar1E861A/E861A) mice die between E11.75–13.5 of failed hematopoiesis. Strikingly this phenotype is rescued by the deletion of the cytosolic dsRNA sensor MDA5 or its downstream adaptor MAVS, a mechanism conserved in human and mouse. Current literature indicates that the loss of ADAR1 leads to cell death via apoptosis, yet this has not been genetically established. We report that blockade of the intrinsic (mitochondrial) apoptosis pathway, through the loss of both BAK and BAX, does not rescue or modify the cellular phenotype of the fetal liver or extend the lifespan of ADAR1 editing deficient embryos. We had anticipated that the loss of BAK and BAX would rescue, or at least significantly extend, the gestational viability of Adar1E861A/E861A embryos. However, the triple mutant Adar1E861A/E861ABak−/−Bax−/− embryos that were recovered at E13.5 were indistinguishable from the Adar1E861A/E861A embryos with BAK and BAX. The results indicate that cell death processes not requiring the intrinsic apoptosis pathway are triggered by MDA5 following the loss of ADAR1.

scholarly journals High expression of anti-apoptotic genes in grade I and II meningiomas

2017 ◽  
Vol 75 (4) ◽  
pp. 209-215 ◽  
Author(s):  
Daniela Pretti da Cunha Tirapelli ◽  
Sarah Bomfim Menezes ◽  
Indira Maynart Franco ◽  
Isis Lacrose Lustosa ◽  
Andressa Romualdo Rodrigues ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Control Group ◽  
Intrinsic Apoptosis ◽  
Extrinsic Pathway ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway ◽  
Apoptosis Pathways ◽  
Genetic Mechanisms ◽  
Apoptotic Genes ◽  
Low Expression

ABSTRACT One of the different genetic mechanisms involved in the carcinogenesis of meningiomas is influenced by interactions between proteins that induce and inhibit apoptosis. Objective To evaluate the expression of c-FLIP, XIAP, Bcl-2, caspase 3, 8 and 9, cytochrome c, APAF 1 and Smac/DIABLO genes related to apoptosis pathways. Methods The gene expression was evaluated in 30 meningiomas (WHO grades I and II) and in 10 normal samples (from arachnoid tissue) through PCR-RT. Results The results showed higher expression of anti-apoptotic genes in meningiomas when compared to the control group, which had a low expression of pro-apoptotic genes. Conclusion There is a possible block in the activation of caspases through the intrinsic apoptosis pathway in meningiomas. c-FLIP modulates caspase 8 and, by inhibiting its activation due to the lack of connection with the receiver, there is a block to the FAS activation of apoptosis by its extrinsic pathway.

Preclinical Evaluation of the Proteasome Inhibitor MLN9708 (MLN2238) In Chronic Lymphocytic Leukemia Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4634-4634
Author(s):  
Aisha Masood ◽  
Kiersten M Miles ◽  
Nazmul H Khan ◽  
Drusilla Akhtar ◽  
Remi Adelaiye ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Proteasome Inhibitor ◽  
Active Form ◽  
Lymphocytic Leukemia ◽  
Biologically Active ◽  
Autologous Serum ◽  
Mitochondrial Outer Membrane ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Abstract Abstract 4634 The proteasome is an important therapeutic target in multiple hematological malignancies. The proteasome inhibitor bortezomib has demonstrated significant clinical activity in multiple myeloma and mantle cell lymphoma. However, clinically bortezomib has failed to demonstrate efficacy in chronic lymphocytic leukemia (CLL); the exact reason for this remains unknown. MLN9708 (Millennium Pharmaceuticals, Inc., Cambridge, MA) is a proteasome inhibitor which has a shorter proteasome dissociation half life than bortezomib and is currently in Phase I clinical development. Upon exposure to aqueous solutions or plasma, MLN9708 rapidly hydrolyzes to MLN2238, the biologically active form. MLN2238 was used for all of the studies reported here, in which we evaluated the antileukemic effects of MLN2238 in primary CLL cells from 16 patients. MLN 2238 induced a time and dose dependent decrease in CLL cell viability in 12 (75%) patient cells in vitro. Cell death was shown to be due to the induction of apoptosis confirmed by Annexin V staining of CLL cells and cleavage of PARP-1, an indicator of apoptosis. Biochemical analysis showed that caspase 3 and 9 were activated in these cells, indicating that MLN2238 induces cell death through the intrinsic apoptosis pathway. We noted increased mitochondrial outer membrane permeability (MOMP) in the presence of MLN2238, which suggests the engagement of the mitochondria in MLN2238 induced apoptosis in CLL cells. Evaluation of non-responding CLL patient samples demonstrated that increased expression of PSMB5 is associated with lack of sensitivity to MLN2238. Furthermore, incremental addition of autologous serum in responding CLL samples resulted in upregulation of PSMB5 levels, resulting in protection against MLN2238 induced cell death. Our preclinical observations demonstrate for the first time that MLN2238 can induce death in primary CLL cells, and support further investigation in CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a GαsProtein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death

2014 ◽  
Vol 35 (2) ◽  
pp. 479-495 ◽  
Author(s):  
Marie Tosolini ◽  
Frédéric Pont ◽  
Delphine Bétous ◽  
Emmanuel Ravet ◽  
Laetitia Ligat ◽  
...  
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Mitochondrial Permeability Transition ◽  
Human Monocyte ◽  
Inverse Agonist ◽  
Apoptotic Pathway ◽  
Cyclic Dinucleotides ◽  
Agonist Ligands

Cyclic dinucleotides are important messengers for bacteria and protozoa and are well-characterized immunity alarmins for infected mammalian cells through intracellular binding to STING receptors. We sought to investigate their unknown extracellular effects by adding cyclic dinucleotides to the culture medium of freshly isolated human blood cellsin vitro. Here we report that adenosine-containing cyclic dinucleotides induce the selective apoptosis of monocytes through a novel apoptotic pathway. We demonstrate that these compounds are inverse agonist ligands of A2a, a Gαs-coupled adenosine receptor selectively expressed by monocytes. Inhibition of monocyte A2a by these ligands induces apoptosis through a mechanism independent of that of the STING receptors. The blockade of basal (adenosine-free) signaling from A2a inhibits protein kinase A (PKA) activity, thereby recruiting cytosolic p53, which opens the mitochondrial permeability transition pore and impairs mitochondrial respiration, resulting in apoptosis. A2a antagonists and inverse agonist ligands induce apoptosis of human monocytes, while A2a agonists are antiapoptotic.In vivo, we used a mock developing human hematopoietic system through NSG mice transplanted with human CD34+cells. Treatment with cyclic di-AMP selectively depleted A2a-expressing monocytes and their precursors via apoptosis. Thus, monocyte recognition of cyclic dinucleotides unravels a novel proapoptotic pathway: the A2a Gαsprotein-coupled receptor (GPCR)-driven tonic inhibitory signaling of mitochondrion-induced cell death.

scholarly journals Characterization of cell-death pathways in Punta Toro virus-induced hepatocyte injury

2008 ◽  
Vol 89 (9) ◽  
pp. 2175-2181 ◽  
Author(s):  
Fangling Xu ◽  
Xiaodong Liang ◽  
Robert B. Tesh ◽  
Shu-Yuan Xiao
Keyword(s):  
Cell Death ◽  
Hepg2 Cells ◽  
Antigen Expression ◽  
Mitochondrial Pathway ◽  
Cellular Viability ◽  
Tnf Receptor ◽  
Extrinsic Pathway ◽  
Punta Toro Virus

Punta Toro virus (PTV; genus Phlebovirus, family Bunyaviridae) causes apoptosis of hepatocytes in vivo in experimentally infected hamsters and in vitro in cultured HepG2 cells. Screening for expression of apoptosis-related genes has shown alterations in the genes for tumour necrosis factor-α (TNF-α) and the TNF receptor family. This study examined the roles of the TNF receptor-related extrinsic pathway and the Bcl-2 family-associated mitochondrial pathway in PTV-induced cell death. The effects of caspase inhibitors (caspIs) and TNF on cellular viability, virus replication, and morphological and biochemical changes in apoptosis were examined in HepG2 cells at different time points after infection with PTV (Adames strain). The results showed that caspIs dampened the virus-induced reduction in cellular viability, partially suppressed and delayed viral titres and antigen expression, and partially decreased the expression of apoptotic genes, caspase activities and DNA fragmentation. TNF treatment further decreased cellular viability after PTV infection and increased the level of apoptosis, whilst caspIs partially inhibited these effects. These findings indicate that TNF, caspase-8 and caspase-9 contribute to PTV-induced hepatocytic apoptosis and that additional mediators are probably also involved in this process. These mediators from different pathways correlated with one another and may be interlinked.

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