scholarly journals Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

2020 ◽  
Author(s):  
Wanfeng Xu ◽  
Yuan Che ◽  
Quan Zhang ◽  
Hai Huang ◽  
Chujie Ding ◽  
...  
Keyword(s):  
Bile Acids ◽  
Caspase 3 ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Calcium Overload ◽  
List Type ◽  
Adenine Nucleotide Translocator ◽  
Mitochondrial Permeability ◽  
Adenine Nucleotide Translocator 1

SUMMARYCaspase-4 directly senses and is activated by cytosolic LPS in conditions of pathogen infection. It is unclear whether and how caspase-4 detects host derived factors for triggering pyroptosis. Here we show that mitochondrial permeability transition (MPT) promotes the assembly of a protein complex comprised of Apaf-1 and caspase-4 (caspase-11 in mice), defined herein as pyroptosome, for the execution of facilitated pyroptosis. MPT induced by bile acids and calcium overload, and specifically by an adenine nucleotide translocator 1 (ANT1) activator, triggered pyroptosome assembly. Different from the direct cleavage of GSDMD by LPS-activated caspase-4, caspase-4 activated in the Apaf-1 pyroptosome proceeds to cleave caspase-3 and thereby gasdermin E (GSDME) to induce pyroptosis. Caspase-11 initiated and GSDME executed pyroptosis underlies cholesteric liver failure. These findings identify Apaf-1 pyroptosome as a pivotal machinery for cells sensing MPT signals and may shed lights on understanding how cells execute pyroptosis under sterile conditions.HighlightsBile acids trigger caspase-4/11 and GSDME dependent pyroptosisCaspase-4/11 is a general sensor of mitochondrial permeability transition (MPT)MPT drives Apaf-1/capase-4 pryoptosome assemblyCaspase-11 and GSDME mediated pyroptosis underlies cholesteric liver damageeTOC BlurbPersistent mitochondrial permeability transition elicited by bile acids, calcium overload and specifically ANT1 activators drives assembly of Apaf-1-capase-4/11 pyroptosome triggering GSDME dependent pryroptosis.

scholarly journals Calcium preconditioning inhibits mitochondrial permeability transition and apoptosis

2001 ◽  
Vol 280 (2) ◽  
pp. H899-H908 ◽  
Author(s):  
Meifeng Xu ◽  
Yigang Wang ◽  
Kyoji Hirai ◽  
Ahmar Ayub ◽  
Muhammad Ashraf
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Cytochrome C Release ◽  
Mitochondrial Permeability ◽  
Lactate Dehydrogenase Release ◽  
Viable Cells ◽  
Reoxygenation Injury ◽  
Injury Protection

We tested the hypothesis whether calcium preconditioning (CPC) reduces reoxygenation injury by inhibiting mitochondrial permeability transition (MPT). Cultured myocytes were preconditioned by a brief exposure to 1.5 mM calcium (CPC) and subjected to 3 h of anoxia followed by 2 h of reoxygenation (A-R). Myocytes were also treated with 0.2 μM/l cyclosporin A (CsA), an inhibitor of MPT, before A-R. A significant increase of viable cells and reduced lactate dehydrogenase release was observed both in CPC- and CsA-treated myocytes compared with the A-R group. Cytochrome c release was predominantly observed in the cytoplasm of myocytes in the A-R group in contrast with CPC- or CsA-treated groups, where it was restricted only to mitochondria. Similarly, the cell death by apoptosis was also markedly attenuated in these groups. Electron-dense Ca2+ deposits in mitochondria were also less frequent. Atractyloside (20 μM/l), an adenine nucleotide translocase inhibitor, caused changes similar to those in the A-R group, suggesting a role of MPT in A-R injury. Protection by inhibition of MPT by CsA and CPC suggests that MPT plays an important role in reoxygenation/reperfusion injury. The data further suggest that preconditioning inhibits MPT by inhibiting Ca2+accumulation by mitochondria.

scholarly journals Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis

2004 ◽  
Vol 383 (1) ◽  
pp. 101-109 ◽  
Author(s):  
Yanmin LI ◽  
Nicholas JOHNSON ◽  
Michela CAPANO ◽  
Mina EDWARDS ◽  
Martin CROMPTON
Keyword(s):  
Oxidative Stress ◽  
Cell Injury ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Intact Cells ◽  
Inner Membrane ◽  
Mitochondrial Permeability ◽  
Apoptosis And Necrosis

Cyclophilin-D is a peptidylprolyl cis–trans isomerase of the mitochondrial matrix. It is involved in mitochondrial permeability transition, in which the adenine nucleotide translocase of the inner membrane is transformed from an antiporter to a non-selective pore. The permeability transition has been widely considered as a mechanism in both apoptosis and necrosis. The present study examines the effects of cyclophilin-D on the permeability transition and lethal cell injury, using a neuronal (B50) cell line stably overexpressing cyclophilin-D in mitochondria. Cyclophilin-D overexpression rendered isolated mitochondria far more susceptible to the permeability transition induced by Ca2+ and oxidative stress. Similarly, cyclophilin-D overexpression brought forward the onset of the permeability transition in intact cells subjected to oxidative stress. In addition, in the absence of stress, the mitochondria of cells overexpressing cyclophilin-D maintained a lower inner-membrane potential than those of normal cells. All these effects of cyclophilin-D overexpression were abolished by cyclosporin A. It is concluded that cyclophilin-D promotes the permeability transition in B50 cells. However, cyclophilin-D overexpression had opposite effects on apoptosis and necrosis; whereas NO-induced necrosis was promoted, NO- and staurosporine-induced apoptosis were inhibited. These findings indicate that the permeability transition leads to cell necrosis, but argue against its involvement in apoptosis.

scholarly journals Aromatase Deficiency Inhibits the Permeability Transition in Mouse Liver Mitochondria

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1643-1652 ◽  
Author(s):  
Loredana Moro ◽  
Arnaldo A. Arbini ◽  
Jer-Tsong Hsieh ◽  
Jeffery Ford ◽  
Evan R. Simpson ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Mitochondrial Protein ◽  
Permeability Transition ◽  
Liver Mitochondria ◽  
Estrogen Deficiency ◽  
Mrna Levels ◽  
Mitochondrial Membranes ◽  
Mitochondrial Permeability

Lack of estrogens affects male physiology in a number of ways, including severe changes in liver metabolism that result in lipid accumulation and massive hepatic steatosis. Here we investigated whether estrogen deficiency may alter the functionality and permeability properties of liver mitochondria using, as an experimental model, aromatase knockout (ArKO) male mice, which cannot synthesize endogenous estrogens due to a disruption of the Cyp19 gene. Liver mitochondria isolated from ArKO mice displayed increased activity of the mitochondrial respiratory complex IV compared with wild-type mice and were less prone to undergo cyclosporin A-sensitive mitochondrial permeability transition (MPT) induced by calcium loading. The altered permeability properties of the mitochondrial membranes were not due to changes in reactive oxygen species, ATP levels, or mitochondrial membrane potential but were associated with increased content of the phospholipid cardiolipin, structural component of the mitochondrial membranes and regulator of the MPT pore, and with increased mitochondrial protein levels of Bcl-2 and the adenine nucleotide translocator (ANT), regulator and component of the MPT pore, respectively. Real-time RT-PCR demonstrated increased mRNA levels for Bcl-2 and ANT2 but not for the ANT1 isoform in ArKO livers. Supplementation of 17β-estradiol retrieved ArKO mice from massive hepatic steatosis and restored mitochondrial permeability properties, cardiolipin, Bcl-2, and ANT2 levels. Overall, our findings demonstrate an important role of estrogens in the modulation of hepatic mitochondrial function and permeability properties in males and suggest that estrogen deficiency may represent a novel positive regulator of Bcl-2 and ANT2 proteins, two inhibitors of MPT occurrence and powerful antiapoptotic molecules.

scholarly journals The Mitochondrial Permeability Transition Is Required for Tumor Necrosis Factor Alpha-Mediated Apoptosis and Cytochrome c Release

1998 ◽  
Vol 18 (11) ◽  
pp. 6353-6364 ◽  
Author(s):  
Cynthia A. Bradham ◽  
Ting Qian ◽  
Konrad Streetz ◽  
Christian Trautwein ◽  
David A. Brenner ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Necrosis ◽  
Caspase 3 ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Necrosis Factor Alpha ◽  
Mitochondrial Permeability ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT This study assesses the controversial role of the mitochondrial permeability transition (MPT) in apoptosis. In primary rat hepatocytes expressing an IκB superrepressor, tumor necrosis factor alpha (TNFα) induced apoptosis as shown by nuclear morphology, DNA ladder formation, and caspase 3 activation. Confocal microscopy showed that TNFα induced onset of the MPT and mitochondrial depolarization beginning 9 h after TNFα treatment. Initially, depolarization and the MPT occurred in only a subset of mitochondria; however, by 12 h after TNFα treatment, virtually all mitochondria were affected. Cyclosporin A (CsA), an inhibitor of the MPT, blocked TNFα-mediated apoptosis and cytochrome c release. Caspase 3 activation, cytochrome c release, and apoptotic nuclear morphological changes were induced after onset of the MPT and were prevented by CsA. Depolarization and onset of the MPT were blocked in hepatocytes expressing ΔFADD, a dominant negative mutant of Fas-associated protein with death domain (FADD), or crmA, a natural serpin inhibitor of caspases. In contrast, Asp-Glu-Val-Asp-cho, an inhibitor of caspase 3, did not block depolarization or onset of the MPT induced by TNFα, although it inhibited cell death completely. In conclusion, the MPT is an essential component in the signaling pathway for TNFα-induced apoptosis in hepatocytes which is required for both cytochrome c release and cell death and functions downstream of FADD and crmA but upstream of caspase 3.

Fas-independent mitochondrial damage triggers cardiomyocyte death after ischemia-reperfusion

2005 ◽  
Vol 289 (5) ◽  
pp. H2153-H2158 ◽  
Author(s):  
L. Gomez ◽  
N. Chavanis ◽  
L. Argaud ◽  
L. Chalabreysse ◽  
O. Gateau-Roesch ◽  
...  
Keyword(s):  
Infarct Size ◽  
Caspase 3 ◽  
Fas Ligand ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Minor Role ◽  
Mitochondrial Permeability ◽  
Mptp Opening

The Fas/Fas ligand and mitochondria pathways have been involved in cell death in several cell types. We combined the genetic inactivation of the Fas receptor ( lpr mice), on the one hand, to the pharmacological inhibition of the mitochondrial permeability transition pore (mPTP), on the other hand, to investigate which of these pathways is predominantly activated during prolonged ischemia-reperfusion. Anesthetized C57BL/6JICO (control) and C57BL/6- lpr mice were pretreated with either saline or cyclosporin A (CsA; 40 mg/kg, 3 times a day), an inhibitor of the mPTP, and underwent 25 min of ischemia and 24 h of reperfusion. After 24 h of reperfusion, hearts were harvested: infarct size was assessed by 2,3,5-triphenyltetrazolium chloride staining, myocardial apoptosis by caspase 3 activity, and mitochondrial permeability transition by Ca2+-induced mPTP opening using a potentiometric approach. Infarct size was comparable in untreated control and lpr mice, ranging from 77 ± 5% to 83 ± 3% of the area at risk. CsA significantly reduced infarct size in control and lpr hearts. Control and lpr hearts exhibited comparable increase in caspase 3 activity that averaged 57 ± 18 and 49 ± 5 pmol·min−1·mg−1, respectively. CsA treatment significantly reduced caspase 3 activity in control and lpr hearts. The Ca2+ overload required to open the mPTP was decreased to a similar extent in lpr and controls. CsA significantly attenuated Ca2+-induced mPTP opening in both groups. Our results suggest that the Fas pathway likely plays a minor role, whereas mitochondria are preferentially involved in mice cardiomyocyte death after a lethal ischemia-reperfusion injury.

scholarly journals Mechanisms Involved in Cardioprotective Effects of Pravastatin Administered during Reoxygenation in Human Myocardium In Vitro 

2012 ◽  
Vol 116 (4) ◽  
pp. 824-833 ◽  
Author(s):  
Sandrine Lemoine ◽  
Stéphane Allouche ◽  
Laurent Coulbault ◽  
Valérie Cornet ◽  
Massimo Massetti ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Human Myocardium ◽  
Control Group ◽  
Force Of Contraction ◽  
Mitochondrial Permeability ◽  
Oxide Synthase

Background The authors investigated the effect of pravastatin during reoxygenation after myocardial hypoxia and examined the involvement of nitric oxide synthase, mitochondrial permeability transition pore, and expression of markers of apoptosis in human myocardium in vitro. Methods Human atrial trabeculae were exposed to hypoxia for 30 min and reoxygenation for 60 min (control group; n = 10). Pravastatin (5, 10, 50, 75 μM; n = 6 in each group) was administered throughout the reoxygenation. In separate groups (n = 6 in each group), pravastatin 50 μM was administered in the presence of 200 μM L-NG-nitroarginine methyl ester, a nitric oxide synthase inhibitor, and 50 μM atractyloside, the mitochondrial permeability transition pore opener. The primary endpoint was the developed force of contraction at the end of reoxygenation, expressed as a percentage of baseline (mean ± SD). Protein expression of BAD, phospho-BAD, caspase 3, Pim-1 kinase, and Bcl-2 were measured using Western immunoblotting. Results The administration of 10 (77 ± 5% of baseline), 50 (86 ± 6%), and 75 μM (88 ± 13%) pravastatin improved the force of contraction at the end of reoxygenation, compared with that of the control group (49 ± 11%; P < 0.001). These beneficial effects were prevented by L-NG-nitroarginine methyl ester and atractyloside. Compared with control group, the administration of 5 μM pravastatin did not modify the force of contraction. Pravastatin increased the phosphorylation of BAD, activated the expression of Pim-1 kinase and Bcl-2, and maintained the caspase 3 concentration relative to that of the respective untreated controls. Conclusions Pravastatin, administered at reoxygenation, protected the human myocardium by preventing the mitochondrial permeability transition pore opening, phosphorylating BAD, activating nitric oxide synthase, Pim-1 kinase, and Bcl-2, and preserving the myocardium against the caspase 3 activation.

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