Reactive γ-ketoaldehydes formed via the isoprostane pathway disrupt mitochondrial respiration and calcium homeostasis
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Mitochondrial apoptosis-induced channel
Apoptosome
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Objective To study the effect of mitochondrial permeability transition(MPT) after ischemia/reperfusion(I/R), and to find the relationship between MPT and apoptosis of hepatocytes in rats. Methods SD rats were divided into three groups:sham operation group, I/R group, and I/R+CsA group. A model of hepatic I/R in rats was made according to the method of Nauta. Active caspase-3 in cytoplasm was examined by immunohistochemistry, and the content of cytochrome C protein was evaluated by Western blotting. The incidence of apoptic hepatocytes was determined by TUNEL method. Cyclosporine A(10 mg·kg -1·d -1) was used as an inhibitor of MPT owing to its inhibitive effect on mitochondrial permeability transition pore(PT pore), and the influences of CsA were analyzed. Results Pretreated with CsA ameliorated injury after reperfusion. The number of apoptotic liver cells was decreased. CsA significantly prevented the release of cytochrome C from mitochondria, demonstrating its effect on MPT through preventing PT pore from opening. Conclusion MPT may play a key role in the apoptosis of liver cell after I/R. CsA, a powerful inhibitor of PT pore, is capable of abating the effect of MPT, reducing the release of cytochrome C, retarding the activation of caspase-3 and hence ameliorates apoptosis of hepatocytes following I/R procedure.
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Apoptosome
Inducer
Mitochondrial apoptosis-induced channel
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Mitochondrial apoptosis-induced channel
Apoptosome
Apoptosis-inducing factor
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Bcl-2 family members either promote or repress programmed cell death. Bax, a death-promoting member, is a pore-forming, mitochondria-associated protein whose mechanism of action is still unknown. During apoptosis, cytochrome C is released from the mitochondria into the cytosol where it binds to APAF-1, a mammalian homologue of Ced-4, and participates in the activation of caspases. The release of cytochrome C has been postulated to be a consequence of the opening of the mitochondrial permeability transition pore (PTP). We now report that Bax is sufficient to trigger the release of cytochrome C from isolated mitochondria. This pathway is distinct from the previously described calcium-inducible, cyclosporin A-sensitive PTP. Rather, the cytochrome C release induced by Bax is facilitated by Mg2+ and cannot be blocked by PTP inhibitors. These results strongly suggest the existence of two distinct mechanisms leading to cytochrome C release: one stimulated by calcium and inhibited by cyclosporin A, the other Bax dependent, Mg2+ sensitive but cyclosporin insensitive.
Apoptosome
Bcl-2-associated X protein
Mitochondrial apoptosis-induced channel
Voltage-dependent anion channel
Bcl-2 Family
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Apoptosome
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Costunolide is an active compound isolated from the root of Saussurea lappa Clarks, a Chinese medicinal herb, and is considered a therapeutic candidate for various types of cancers. Nevertheless, the pharmacological pathways of costunolide are still unknown. In this study, we investigate the effects of costunolide on the induction of apoptosis in HL-60 human leukemia cells and its putative pathways of action. Using apoptosis analysis, measurement of reactive oxygen species (ROS), and assessment of mitochondrial membrane potentials, we show that costunolide is a potent inducer of apoptosis, and facilitates its activity via ROS generation, thereby inducing mitochondrial permeability transition (MPT) and cytochrome c release to the cytosol. ROS production, mitochondrial alteration, and subsequent apoptotic cell death in costunolide-treated cells were blocked by the antioxidant N-acetylcystein (NAC). Cyclosporin A, a permeability transition inhibitor, also inhibited mitochondrial permeability transition and apoptosis. Our data indicate that costunolide induces the ROS-mediated mitochondrial permeability transition and resultant cytochrome c release. This is the first report on the mechanism of the anti-cancer effect of costunolide.
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Mitochondrial apoptosis-induced channel
Apoptosome
Organelle
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Objective
To explore the influence of mitochondrial permeability transition pore opening and cytochrome C(Cyt C) being discharged on the apoptotic mechanism of HL-60 cell induced by desferrioxamine(DFO), so as to provide scientific basis for the clinicians to adopt the strategy of iron deprivation to treat human leukemia.
Methods
HL-60 cells were co-cultivated with various concentration of DFO for 24-72 hours, then the apoptotic cells and the changes of mitochondrial membrane potential(ΔΨm) were examined by means of flow cytometry(FCM), and Cyt C in cytoplasm was detected by way of celluar immunohistochemistry.
Results
The cell apoptotic rate assumed rising ten-dency as the highest rate could be up to(44.10±6.31)%, and the effect was of time-and-dose dependence(P<0.01). FCM could detect the ΔΨm declining(P<0.05), and the Cyt C positive cell rate was higher than the controls, the differences were of statistical significance(P<0.05).
Conclusions
DFO can induce the HL-60 cells apoptosis, and the possible mechanism is that DFO make the mitochondrial permeability transition pore open and get Cyt C discharged from the mitochondria.
Key words:
Desferrioxamine; HL-60 cell; Apoptosis; Mitochondrion membrane potential; Cytochrome C
Apoptosome
Mitochondrial apoptosis-induced channel
Membrane permeability
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