Postnatal brain development and neural cell differentiation modulate mitochondrial Bax and BH3 peptide-induced cytochrome c release
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Mitochondrial apoptosis-induced channel
Apoptosome
In a cell-free apoptosis system, mitochondria spontaneously released cytochrome c, which activated DEVD-specific caspases, leading to fodrin cleavage and apoptotic nuclear morphology. Bcl-2 acted in situ on mitochondria to prevent the release of cytochrome c and thus caspase activation. During apoptosis in intact cells, cytochrome c translocation was similarly blocked by Bcl-2 but not by a caspase inhibitor, zVAD-fmk. In vitro, exogenous cytochrome c bypassed the inhibitory effect of Bcl-2. Cytochrome c release was unaccompanied by changes in mitochondrial membrane potential. Thus, Bcl-2 acts to inhibit cytochrome c translocation, thereby blocking caspase activation and the apoptotic process.
Apoptosome
Mitochondrial apoptosis-induced channel
Intrinsic apoptosis
Caspase-9
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Preservation of Mitochondrial Structure and Function after Bid- or Bax-Mediated Cytochrome c Release
Proapoptotic members of the Bcl-2 protein family, including Bid and Bax, can activate apoptosis by directly interacting with mitochondria to cause cytochrome c translocation from the intermembrane space into the cytoplasm, thereby triggering Apaf-1–mediated caspase activation. Under some circumstances, when caspase activation is blocked, cells can recover from cytochrome c translocation; this suggests that apoptotic mitochondria may not always suffer catastrophic damage arising from the process of cytochrome c release. We now show that recombinant Bid and Bax cause complete cytochrome c loss from isolated mitochondria in vitro, but preserve the ultrastructure and protein import function of mitochondria, which depend on inner membrane polarization. We also demonstrate that, if caspases are inhibited, mitochondrial protein import function is retained in UV-irradiated or staurosporine-treated cells, despite the complete translocation of cytochrome c. Thus, Bid and Bax act only on the outer membrane, and lesions in the inner membrane occurring during apoptosis are shown to be secondary caspase-dependent events.
Mitochondrial apoptosis-induced channel
Apoptosome
Intermembrane space
Staurosporine
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There is an evidence that mitochondrial cytochrome C has dual functions in controlling both cellular energetic metabolism and apoptosis. Once released, cytochrome C, in interaction with apoptotic protease activating factors (Apaf 1), initiates the activation of the execution caspases that lead to the subsequent apoptosis. Release of cytochrome C is the result of a perturbation of mitochondrial membrane permeability. Anti apoptotic Bcl 2 family proteins function as gatekeepers to prevent the release of cytochrome C. In addition to cytochrome C, mitochondria release other apoptogenic proteins including apoptosis inducing factor (AIF) during apoptosis. These two pathways may work together to induce complete apoptosis. After transient cerebral ischemia, the release of cytochrome C occurs from mitochondria, preceding DNA fragmentation.
Apoptosome
Mitochondrial apoptosis-induced channel
Intrinsic apoptosis
Apoptosis-inducing factor
Bcl-2 Family
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Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.
Apoptosome
Mitochondrial apoptosis-induced channel
Intermembrane space
Mitochondrial intermembrane space
Cytochrome C1
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Mitochondrial apoptosis-induced channel
Apoptosome
Intrinsic apoptosis
Apoptosis-inducing factor
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British Journal of Pharmacology (2002) 136, 1081–1082. doi:10.1038/sj.bjp.0704822 Apoptosis is a form of cell death characterized by the activation of caspases (cystenyl aspartate specific proteases) that cleave multiple targets in the cell. The control of caspase activation represents a major decision point for determining whether a cell will either continue to live or die by apoptosis. The release of cytochrome c from mitochondria as a result of permeability changes to the mitochondrial membranes is an important pathway of caspase activation in some forms of apoptosis (reviewed by Desagher & Martinou, 2000; Gottlieb, 2000). Cytochrome c binds with apaf-1, ATP and procaspases in the cytoplasm to form apoptosome complexes that activate caspase 9, and in turn, other caspases. The mechanisms that control mitochondrial membrane permeability and the release of cytochrome c during apoptosis are becoming better understood, but are still controversial. For example, the bcl-2 family of proteins displays anti-apoptotic and pro-apoptotic functions possibly by targeting the outer membranes of mitochondria, preventing or promoting the formation of cytochrome c permeant pores. Opening of the mitochondrial permeability transition pore complex at contact sites of the inner and outer membranes may also cause the release of cytochrome c from the inter-membrane space, by allowing entry of water and solutes, inducing mitochondrial swelling and causing the rupture of the less expansive outer membrane. Thus, over the last few years mitochondria have become known for promoting apoptosis and activating caspases by undergoing membrane permeability changes and releasing cytochrome c. There is now considerable interest in the potential to manipulate the mitochondrial regulation of apoptosis for therapeutic gain. For example, the induction of mitochondrial pathways to apoptosis could be used to eliminate diseased cells from the body in cancer chemotherapy (Costantini et al., 2000). In the most advanced approach of this type, Genasense (G3139), an antisense oligonucleotide complementary to bcl-2 mRNA, is being applied to down-regulate expression of the bcl-2 antiapoptotic protein on mitochondrial membranes. In clinical trials, Genasense therapy has been shown to be feasible and well tolerated, and to achieve down-regulation of bcl-2 protein in tumour samples, and clinical antitumour responses (Waters et al., 2000). Mitochondria are therefore becoming clinically validated targets for cancer chemotherapy. The same mitochondrial pathways are also of interest as drug targets for therapies aiming to prevent membrane permeability changes and the loss of cells from the body (Morin et al., 2001). Auranofin and other gold (I) complexes are well known as anti-arthritic drugs, but also inhibit the growth of cultured tumour cells in vitro and many have antimitochondrial activity (reviewed in McKeage et al., 2002). Early studies of auranofin showed accumulation of tumour cellular debris in lower channels of flow cytometry DNA histograms and morphological changes (Mirabelli et al., 1985). In retrospect this is consistent with an in vitro antitumour mechanism involving the induction of apoptosis rather than growth arrest of cycling cells. Although the intracellular targets of auranofin and gold (I) complex are unclear, auranofin has recently become known as a potent and specific inhibitor of thioredoxin reductase (Gromer et al., 1998), an enzyme that may play an important role in the redox control of the permeability of mitochondrial membranes (Rigobello et al., 1998). A paper in this issue of the British Journal of Pharmacology, by Rigobello et al. (2002) provides further linkages between the thioredoxin reductase/thioredoxin system, mitochondrial membrane permeability transition and the biological activities of auranofin and other gold (I) complexes. Auranofin is shown to be a potent inducer of swelling of freshly isolated rat liver mitochondria, indicative of a transition in the permeability status of the mitochondrial membranes. Inhibition of the effect of auranofin on mitochondrial permeability by cyclosporin A and other experimental conditions inferred a mechanism involving the mitochondrial permeability transition pore complex.Permeability changes were shown to occur at auranofin concentrations associated with the selective inhibition of mitochondrial thioredoxin reductase, and with few effects on the mitochondrial electron transport chain or glutathione reductase. In summary, over the last few years mitochondria have become known for promoting apoptosis by releasing cytochrome c and other pro-apoptotic factors during mitochondrial permeability transition or via other release mechanisms. There is now considerable interest in the therapeutic potential of manipulating mitochondrial membrane permeability in order to prevent or promote cell death. One of the targets under investigation is the redox control of mitochondrial permeability transition that may depend upon the thioredoxin reductase/thioredoxin system. Gold drugs like auranofin are known for inhibiting thioredoxin reductase and for suppressing the growth of cultured tumour cells. Hence, the demonstration by Rigobello et al. (1998) that auranofin is a potent inducer of mitochondrial permeability transition, through the inhibition of mitochondrial thioredoxin reductase is a significant finding because it strengthens the links between the thioredoxin reductase/thioredoxin system, mitochondrial permeability transition and the cell killing properties of auranofin and other gold (I) complexes.
Apoptosome
Mitochondrial apoptosis-induced channel
Intrinsic apoptosis
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MT-21 is a synthetic apoptosis inducer that directly induces cytochrome c release from mitochondria.
We reported previously that a synthetic compound, MT-21, induced apoptosis by activating c-Jun-NH2-terminal kinase via the Krs/MST protein, which is activated by caspase-3 cleavage dependent on reactive oxygen species production. Here we examine the activation mechanism of caspase-3, an important cysteine aspartic protease, during MT-21-induced apoptosis. We found that MT-21 activated caspase-3 via caspase-9, but not via caspase-8. In addition, MT-21 induced the release of cytochrome c from the mitochondria that is necessary to activate caspase-9, and this release occurred before a change in membrane potential. This initiation process of MT-21-induced apoptosis was suppressed by overexpression of Bcl-2, which is known to prevent cells from undergoing apoptosis in response to a variety of stimuli. Moreover, when we treated mitochondria isolated from the cells with MT-21, the direct release of cytochrome c from the mitochondria was observed, whereas this effect was not observed in the mitochondria isolated from cells that overexpressed Bcl-2. Other apoptosis-inducing agents known to induce apoptosis via cytochrome c release from the mitochondria failed to release cytochrome c directly from isolated mitochondria. These findings indicate that MT-21 is a possible candidate antitumor agent that is able to induce apoptosis via the direct release of cytochrome c from the mitochondria.
Mitochondrial apoptosis-induced channel
Apoptosome
Caspase-9
Intrinsic apoptosis
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Apoptosome
Mitochondrial apoptosis-induced channel
Sf9
Intrinsic apoptosis
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Apoptosome
Mitochondrial apoptosis-induced channel
Intrinsic apoptosis
Caspase-9
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Bax and Bak promote apoptosis by perturbing the permeability of the mitochondrial outer membrane and facilitating the release of cytochrome c by a mechanism that is still poorly defined. During apoptosis, Bax and Bak also promote fragmentation of the mitochondrial network, possibly by activating the mitochondrial fission machinery. It has been proposed that Bax/Bak-induced mitochondrial fission may be required for release of cytochrome c from the mitochondrial intermembrane space, although this has been a subject of debate. Here we show that Bcl-xL, as well as other members of the apoptosis-inhibitory subset of the Bcl-2 family, antagonized Bax and/or Bak-induced cytochrome c release but failed to block mitochondrial fragmentation associated with Bax/Bak activation. These data suggest that Bax/Bak-initiated remodeling of mitochondrial networks and cytochrome c release are separable events and that Bcl-2 family proteins can influence mitochondrial fission-fusion dynamics independent of apoptosis.
Mitochondrial apoptosis-induced channel
Apoptosome
Intermembrane space
Mitochondrial intermembrane space
Bcl-2 Family
Bcl-2-associated X protein
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