BAX-dependent transport of cytochrome c reconstituted in pure liposomes

Saito, Mitsuyoshi; Korsmeyer, Stanley J.; Schlesinger, Paul H.

doi:10.1038/35019596

Cited by 419 publications

(344 citation statements)

References 23 publications

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“…Results of this study may shed some light on the molecular nature of the releasing mechanism of Cyt-c and Smac. So far, several hypotheses have been proposed for the release of mitochondrial proteins during apoptosis, 22,23 including: (a) Swelling of mitochondrial matrix and rupture of the outer mitochondrial membrane as a result of PT pore opening; 24 (b) Formation of a novel pore by the Bax family proteins in conjunction with the voltage dependent anion channel (VDAC); 19 (c) Formation of channels comprised of Bax family members; 25 (d) Formation of large lipid-protein complexes in the mitochondrial outer membrane comprised mainly of Bax-like proteins. 22,26 The swelling model (i.e., hypothesis a) has already been ruled out by our previous study.…”

Section: Discussionmentioning

confidence: 99%

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Smac/DIABLO and cytochrome c are released from mitochondria through a similar mechanism during UV-induced apoptosis

Zhou

Luo

et al. 2005

Apoptosis

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During apoptosis, a key event is the release of Smac/DIABLO (an inhibitor of XIAP) and cytochrome c (Cyt-c, an activator of caspase-9) from mitochondria to cytosol. It was not clear, however, whether the releasing mechanisms of these two proteins are the same. Using a combination of single living-cell analysis and immunostaining techniques, we investigated the dynamic process of Smac and Cyt-c release during UV-induced apoptosis in HeLa cells. We found that YFP-labeled Smac and GFP-labeled Cyt-c were released from mitochondria in the same time window, which coincided with the mitochondrial membrane potential depolarization. Furthermore, using immunostaining, we found that the endogenous Smac and Cyt-c were always released together within an individual cell. Finally, when cells were pre-treated with caspase inhibitor (z-VAD-fmk) to block caspase activation, the process of Smac release, like that of Cyt-c, was not affected. This was true for both YFPlabeled Smac and endogenous Smac. These results suggest that in HeLa cells, both Smac and Cyt-c are released from mitochondria during UV-induced apoptosis through the same permeability transition mechanism, which we believe is triggered by the aggregation of Bax in the outer mitochondrial membrane to form lipid-protein complex.

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Section: Discussionmentioning

confidence: 99%

“…It is conceivable that such channel may be large enough to pass a small molecule such as Cyt-c (MW=15 kDa). 25 But, the channel would be very difficult to allow Smac to pass through. It is known that the endogenous Smac generally appeared as tetramers in the cellular environment, its molecular weight is about 100 kDa.…”

Section: Discussionmentioning

confidence: 99%

Smac/DIABLO and cytochrome c are released from mitochondria through a similar mechanism during UV-induced apoptosis

Zhou

Luo

et al. 2005

Apoptosis

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“…The architecture of BCL-X L consists of eight a-helices, two of which form a central hydrophobic core reminiscent of the membrane insertion domains of pore-forming Diphtheria toxin and colicins. 72 This structural analogy led to experimental confirmation that BCL-2 family members can mediate pore formation in liposomal and mitochondrial systems, [73][74][75][76] an activity that is dependent upon core helices 5 and 6. [76][77][78] Another critical architectural feature of BCL-X L was identified on its protein surface, a hydrophobic groove formed at the apex by the confluence of BH1, 2, and 3 domains and at the base by a-helices 3 and 4.…”

Section: Bcl-2 Family Form and Functionmentioning

confidence: 99%

BCL-2 in the crosshairs: tipping the balance of life and death

Walensky¹

2006

Cell Death Differ

225

175

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The discovery of B-cell lymphoma-2 (BCL-2) over 20 years ago revealed a new paradigm in cancer biology: the development and persistence of cancer can be driven by molecular roadblocks along the natural pathway to cell death. The subsequent identification of an expansive family of BCL-2 proteins provoked an intensive investigation of the interplay among these critical regulators of cell death. What emerged was a compelling tale of guardians and executioners, each participating in a molecular choreography that dictates cell fate. Ten years into the BCL-2 era, structural details defined how certain BCL-2 family proteins interact, and molecular targeting of the BCL-2 family has since become a pharmacological quest. Although many facets of BCL-2 family death signaling remain a mechanistic mystery, small molecules and peptides that effectively target BCL-2 are eliminating the roadblock to cell death, raising hopes for a medical breakthrough in cancer and other diseases of deregulated apoptosis.

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“…Recombinant Bax can permeabilize liposomal membranes and form channels in planar lipid bilayers. Such studies suggested that Bax alone (Saito et al, 2000) (or associated with VDAC) (Shimizu et al, 1999) would form a conduit selective for small proteins such as cyt c (14.5 kDa). Bax combined with another proapoptotic protein of the Bcl-2 family, t-Bid, can permeabilize cardiolipin-containing liposomes in vitro to fluorescent dextran of size up to 2000 kDa (Kuwana et al, 2002), correlating with the fact that apoptotic MOMP occurring in true cells is nonselective and affects all soluble intermembrane proteins, irrespective of their size (Patterson et al, 2000).…”

Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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BAX-dependent transport of cytochrome c reconstituted in pure liposomes

Cited by 419 publications

References 23 publications

Smac/DIABLO and cytochrome c are released from mitochondria through a similar mechanism during UV-induced apoptosis

Smac/DIABLO and cytochrome c are released from mitochondria through a similar mechanism during UV-induced apoptosis

BCL-2 in the crosshairs: tipping the balance of life and death

Mitochondria as therapeutic targets for cancer chemotherapy

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