Role of the Mitochondrial Permeability Transition and Cytochrome c Release in Hydrogen Peroxide-Induced Apoptosis

Takeyama, Naoshi; Miki, Shigeki; Hirakawa, Akihiko; Tanaka, Takaya

doi:10.1006/excr.2001.5447

Cited by 97 publications

(64 citation statements)

References 41 publications

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“…Treatment with H 2 O 2 can induce cytotoxicity both by apoptosis and by necrosis, depending on its concentration (60,61). Treatment with H 2 O 2 induces the formation of the mitochondrial permeability transition pore and the collapse of mitochondrial membrane potential, thereby triggering apoptosis (59,(62)(63)(64) While the effects of lipophilic PM analogs on HepG2 cells suggest their potential as therapeutic agents, the utility of these compounds will be dependent on whether effective concentrations can be delivered in vivo without toxicity. The concentrations of lipophilic PM analogs used in the HepG2 cell study were relatively high (500 μM), but we did not determine the minimum concentration required for cytoprotection.…”

Section: Discussionmentioning

confidence: 99%

Pyridoxamine Analogues Scavenge Lipid-Derived γ-Ketoaldehydes and Protect against H₂O₂-Mediated Cytotoxicity

et al. 2006

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Isoketals and levuglandins are highly reactive γ-ketoaldehydes formed by oxygenation of arachidonic acid in settings of oxidative injury and cyclooxygenase activation, respectively. These compounds rapidly adduct to proteins via lysyl residues, which can alter protein structure/function. We examined whether pyridoxamine, which has been shown to scavenge α-ketoaldehydes formed by carbohydrate or lipid peroxidation, could also effectively protect proteins from the more reactive γ-ketoaldehydes. Pyridoxamine prevented adduction of ovalbumin and also prevented inhibition of RNase A and glutathione reductase activity by the synthetic γ-ketoaldehyde, 15-E 2 -isoketal. We identified the major products of the reaction of pyridoxamine with the 15-E 2 -isoketal, including a stable lactam adduct. Two lipophilic analogs of pyridoxamine, salicylamine and 5'O-pentylpyridoxamine, also formed lactam adducts when reacted with 15-E 2 -isoketal. When we oxidized arachidonic acid in the presence of pyridoxamine or its analogs, pyridoxamine-isoketal adducts were found in significantly greater abundance than the pyridoxamine-N-acyl adducts formed by α-ketoaldehyde scavenging. Therefore, pyridoxamine and its analogs appear to preferentially scavenge γ-ketoaldehydes. Both pyridoxamine and its lipophilic analogs inhibited the formation of lysyl-levuglandin adducts in platelets activated ex vivo with arachidonic acid. The two lipophilic pyridoxamine analogs provided significant protection against H 2 O 2 -mediated cytotoxicity in HepG2 cells. These results demonstrate the utility of pyridoxamine and lipophilic pyridoxamine analogs to assess the potential contributions of isoketals and levuglandins in oxidant injury and inflammation and suggest their potential utility as pharmaceutical agents in these conditions.Highly reactive γ-ketoaldehydes are formed via the cyclooxygenase pathway and by radicalcatalyzed lipid peroxidation. Prostaglandin H 2 , the product of the cyclooxygenase enzyme, rearranges in aqueous solution to form a number of eicosanoids, approximately 20% of which are the γ-ketoaldehydes levuglandin E 2 and D 2 . Lipid peroxidation yields a series of † This work was supported by National Institutes of Health Grants GM42056 (MERIT Award to L.J.R.), AG26119, GM15431 (to J . NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2008 December 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript prostaglandin H 2 isomers that also rearrange to corresponding γ-ketoaldehydes, designated as isoketals (IsoK). These γ-ketoaldehydes (γKAs) react extremely rapidly with the lysyl residues of protein to form stable adducts, including a lysyl-lactam adduct and intermolecular crosslinks (1-4). Levels of γKA adducts significantly increase in pathological conditions including atherosclerosis, end-stage renal disease, and Alzheimer's Disease (5,6). Increased γKA adduct formation has also been characterized in experimental models of oxidative injury and inflammation, including carb...

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Section: Discussionmentioning

confidence: 99%

Pyridoxamine Analogues Scavenge Lipid-Derived γ-Ketoaldehydes and Protect against H₂O₂-Mediated Cytotoxicity

et al. 2006

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“…EndoG translocates from mitochondria to nuclei in response to apoptotic stimuli, followed by nucleosomal DNA fragmentation; all of these processes (translocation and nucleosomal DNA fragmentation) occur caspaseindependently (40). As mitochondria are one of the main targets of ROS, which can evoke the release of mitochondrial pro-apoptotic proteins through changes in mitochondrial permeability transition (MPT) (57)(58)(59)(60), EndoG is appeared to be the most likely candidate DNase to be involved in apoptotic cell death induced by ATZϩMS. Therefore, we focused on investigating the role of EndoG in this study.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Endonuclease G in Nucleosomal DNA Fragmentation under Sustained Endogenous Oxidative Stress

Ishihara

Shimamoto

2006

Journal of Biological Chemistry

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We have previously shown that inhibition of catalase and glutathione peroxidase activities by 3-amino-1,2,4-triazole (ATZ) and mercaptosuccinic acid (MS), respectively, in rat primary hepatocytes caused sustained endogenous oxidative stress and apoptotic cell death without caspase-3 activation. In this study, we investigated the mechanism of this apoptotic cell death in terms of nucleosomal DNA fragmentation. Treatment with ATZ؉MS time-dependently increased the number of deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL)-positive nuclei from 12 h, resulting in clear DNA laddering at 24 h. The deoxyribonuclease (DNase) inhibitor, aurintricarboxylic acid (ATA), completely inhibited nucleosomal DNA fragmentation but the pan-caspase inhibitor, z-VAD-fmk was without effects; furthermore, the cleavage of inhibitor of caspase-activated DNase was not detected, indicating the involvement of DNase(s) other than caspase-activated DNase. Considering that endonuclease G (EndoG) reportedly acts in a caspase-independent manner, we cloned rat EndoG cDNA for the first time. Recombinant EndoG alone digested plasmid DNA and induced nucleosomal DNA fragmentation in isolated hepatocyte nuclei. Recombinant EndoG activity was inhibited by ATA but not by hydrogen peroxide, even at 10 mM. ATZ؉MS stimulation elicited decreases in mitochondrial membrane potential and EndoG translocation from mitochondria to nuclei. By applying RNA interference, the mRNA levels of EndoG were almost completely suppressed and the amount of EndoG protein was decreased to approximately half the level of untreated cells. Under these conditions, decreases in TUNEL-positive nuclei were significantly suppressed. These results indicate that EndoG is responsible, at least in part, for nucleosomal DNA fragmentation under endogenous oxidative stress conditions induced by ATZ؉MS.

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“…Indeed, ROS such as H 2 O 2 rapidly induce loss of mitochondrial transmembrane potential and cytochrome c release-dependent apoptosis (Ref. 55 and data not shown). Hence, we tested the hypothesis that 15d-PGJ 2 may produce mitochondrial damage in T cells by ROS.…”

Section: D-pgj 2 -Induced Mitochondrial Damage Is Dependent On Oxidmentioning

confidence: 94%

“…After 15 min, cells were harvested, washed, and incubated for 15 min in PBS containing 5 M DCFH-DA. Thereafter, cells were washed and analyzed by flow cytometry (55).…”

Section: Determination Of Reactive Oxygen Species (Ros) Generationmentioning

confidence: 99%

Cyclopentenone Prostaglandins Induce Lymphocyte Apoptosis by Activating the Mitochondrial Apoptosis Pathway Independent of External Death Receptor Signaling

Nencioni

Lauber

Grünebach³

et al. 2003

The Journal of Immunology

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15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2) is a naturally occurring cyclopentenone metabolite of PGD2 that possesses both peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent and PPAR-γ-independent anti-inflammatory properties. Recent studies suggest that cyclopentenone PGs may play a role in the down-regulation of inflammation-induced immune responses. In this study, we report that 15d-PGJ2 as well as synthetic PPAR-γ agonists inhibit lymphocyte proliferation. However, only 15d-PGJ2, but not the specific PPAR-γ activators, induce lymphocyte apoptosis. We found that blocking of the death receptor pathway in Fas-associated death domain−/− or caspase-8−/− Jurkat T cells has no effect on apoptosis induction by 15d-PGJ2. Conversely, overexpression of Bcl-2 or Bcl-xL completely inhibits the initiation of apoptosis, indicating that 15d-PGJ2-mediated apoptosis involves activation of the mitochondrial pathway. In line with these results, 15d-PGJ2 induces mitochondria disassemblage as demonstrated by dissipation of mitochondrial transmembrane potential (Δψm) and cytochrome c release. Both of these events are partially inhibited by the broad spectrum caspase inhibitor benzyloxycarbonil-Val-Ala-Asp-fluoromethylketone, suggesting that caspase activation may amplify the mitochondrial alterations initiated by 15d-PGJ2. We also demonstrate that 15d-PGJ2 potently stimulates reactive oxygen species production in Jurkat T cells, and Δψm loss induced by 15d-PGJ2 is prevented by the reactive oxygen species scavenger N-acetyl-l-cysteine. In conclusion, our data indicate that cyclopentenone PGs like 15d-PGJ2 may modulate immune responses even independent of PPAR-γ by activating the mitochondrial apoptosis pathway in lymphocytes in the absence of external death receptor signaling.

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Role of the Mitochondrial Permeability Transition and Cytochrome c Release in Hydrogen Peroxide-Induced Apoptosis

Cited by 97 publications

References 41 publications

Pyridoxamine Analogues Scavenge Lipid-Derived γ-Ketoaldehydes and Protect against H₂O₂-Mediated Cytotoxicity

Pyridoxamine Analogues Scavenge Lipid-Derived γ-Ketoaldehydes and Protect against H₂O₂-Mediated Cytotoxicity

Involvement of Endonuclease G in Nucleosomal DNA Fragmentation under Sustained Endogenous Oxidative Stress

Cyclopentenone Prostaglandins Induce Lymphocyte Apoptosis by Activating the Mitochondrial Apoptosis Pathway Independent of External Death Receptor Signaling

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Role of the Mitochondrial Permeability Transition and Cytochrome c Release in Hydrogen Peroxide-Induced Apoptosis

Cited by 97 publications

References 41 publications

Pyridoxamine Analogues Scavenge Lipid-Derived γ-Ketoaldehydes and Protect against H2O2-Mediated Cytotoxicity

Pyridoxamine Analogues Scavenge Lipid-Derived γ-Ketoaldehydes and Protect against H2O2-Mediated Cytotoxicity

Involvement of Endonuclease G in Nucleosomal DNA Fragmentation under Sustained Endogenous Oxidative Stress

Cyclopentenone Prostaglandins Induce Lymphocyte Apoptosis by Activating the Mitochondrial Apoptosis Pathway Independent of External Death Receptor Signaling

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Pyridoxamine Analogues Scavenge Lipid-Derived γ-Ketoaldehydes and Protect against H₂O₂-Mediated Cytotoxicity

Pyridoxamine Analogues Scavenge Lipid-Derived γ-Ketoaldehydes and Protect against H₂O₂-Mediated Cytotoxicity