The permeability transition pore triggers Bax translocation to mitochondria during neuronal apoptosis

Precht, Thomas A.; Phelps, Reid A.; Linseman, Daniel A.; Butts, Brent D.; Le, Shoshona S.; Laessig, Tracey A.; Bouchard, Ron J.; Heidenreich, Kim A.

doi:10.1038/sj.cdd.4401552

Cited by 74 publications

(72 citation statements)

References 43 publications

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“…This time frame is sufficient to elicit cytochrome c release 5,6 and BAX translocation to mitochondria. 27 Therefore, BAX translocation to mitochondria is not associated with a permeability transition, 45 although the decreased spare respiratory capacity ( Figure 3, Table 1) would be consistent with partial release of cytochrome c by outer membrane permeabilization.…”

Section: Discussionmentioning

confidence: 99%

“…5,6,37,44 The mechanism of release, whether by activation of the permeability transition pore 6,45 or BAX association with mitochondria 27 is unclear. In the present study, no significant change in oligomycin-insensitive proton leak was evident over 1-5 h of K þ /serum deprivation ( Figure 3, Table 1), despite the ncreasing number of cells showing signs of apoptosis during this period (Table 1).…”

Section: Discussionmentioning

confidence: 99%

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Bioenergetic analysis of cerebellar granule neurons undergoing apoptosis by potassium/serum deprivation

Jekabsons

Nicholls

2006

Cell Death Differ

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Apoptosis induced by K þ /serum deprivation (low K þ ) in cerebellar granule neurons has been extensively investigated. The mitochondria play a key role in apoptosis by releasing proapoptotic factors into the cytoplasm, and mitochondrial dysfunction has been proposed as an early or initiating event in this model. To directly test this hypothesis, cellular and mitochondrial bioenergetics were quantified by determining the respiratory parameters of coverslip-attached neurons. While oxidative phosphorylation rate decreased 39-49% in low K þ , this was due to decreased cellular ATP demand rather than impaired ATP/ADP exchange or respiratory chain inhibition. From 3 to 5 h in low K þ , apoptosis progressed from 13 to 40% despite no appreciable change in respiratory parameters. Changes in steady-state O 2 À , assessed with dihydroethidium, were seen in granule but not hippocampal neurons. The O 2 À change correlated with changes in [Ca 2 þ ] c , but not mitochondrial respiration. Thus, early mitochondrial dysfunction can be excluded in this common model of neuronal apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bioenergetic analysis of cerebellar granule neurons undergoing apoptosis by potassium/serum deprivation

Jekabsons

Nicholls

2006

Cell Death Differ

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“…PTP may also help Bax pore-forming activity (Narita et al, 1998): it has been reported that whenever PTP is open, Bax recruitment from the cytosol to the mitochondrial membrane is facilitated (Precht et al, 2005); in addition, PTP facilitates the acquisition of the correct poreforming supra-molecular assembly of membrane-bound Bax (De Giorgi et al, 2002).…”

Section: Cooperation With the Mitochondrial Permeability Transition Porementioning

confidence: 99%

Multistep and multitask Bax activation

Ghibelli

Diederich

2010

Mitochondrion

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Bax is a pro-apoptotic protein allowing apoptosis to occur through the intrinsic, damage-induced pathway, and amplifying that one occurring via the extrinsic, receptor mediated pathway. Bax is present in viable cells and activated by pro-apoptotic stimuli. Activation implies structural changes, consisting of exposure of the N terminus and hydrophobic domains; changes in localization, consisting in migration from cytosol to mitochondria and endoplasmic reticulum membranes; changes in the aggregation status, from monomer to dimer and multimer. Bax has multiple critical domains, namely the N terminus exposed after activation; two hydrophobic stretches exposed for membrane anchorage; two reactive cysteines allowing multimerization; the BH3 domain for interactions with the Bcl-2 family members; alpha helix 1 for t-Bid interaction. Bax has also multiple functions: it releases different mitochondrial factors such as cytochrome c, SMAC/diablo; it regulates mitochondrial fission, the mitochondrial permeability transition pore; it promotes Ca 2+ leakage through ER membrane. Altogether, Bax activation is a complex multi-step phenomenon. Here, we analyze these events as logically separable or alternative steps, attempting to assess their role, timing and reciprocal relation.

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“…23 Recent evidence has shown that bax apoptotic activity is regulated by translocation of cytoplasmic bax to the mitochondria under apoptotic stimuli. 12,24,25 This translocation is dependent on the conformational change in the C terminus of bax protein by dephosphorylation of serine at position 184 26 and possibly threonine at position 182. 24 The phosphorylation and dephosphorylation of bax have been suggested to be regulated by PKC zeta 27 and PP2A, 28 respectively.…”

Section: Introductionmentioning

confidence: 99%

“…12,24,25 This translocation is dependent on the conformational change in the C terminus of bax protein by dephosphorylation of serine at position 184 26 and possibly threonine at position 182. 24 The phosphorylation and dephosphorylation of bax have been suggested to be regulated by PKC zeta 27 and PP2A, 28 respectively. The objective of this study was to generate a nonviral gene therapy vector with significant and selective activity in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Improved nonviral cancer suicide gene therapy using survivin promoter-driven mutant Bax

et al. 2009

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Suicide gene vectors are being developed in many laboratories as an attractive approach to cancer therapy. However, the development of these therapies is hampered by safety concerns and limitations of efficacy. The use of tumor-specific promoters, such as survivin promoter, can provide much needed specificity to target tumor cells. However, the expression levels from these promoters is often suboptimal and hence it is imperative to enhance the activity of the cytotoxic gene of interest. We tested apoptotic activity of several mutants of proapoptotic gene bax that constitutively translocate to the mitochondria and induce apoptosis. One of these mutants with deletion of serine at position S184 (S184del) was found to be most active and showed significant antitumor activity when expressed by the survivin promoter. In vitro testing shows that this vector (Sur-BaxS184del) induces cell killing in a variety of tumor cell lines of different origin with significantly higher efficacy than wild-type bax (SurBaxWT). The increase in cytotoxicity was a result of enhanced induction of apoptosis in tumor cells. In contrast to cytomegalovirus (CMV) promoter-driven bax (CMV-Bax), Sur-BaxS184del caused minimum toxicity in normal human dermal fibroblasts validating its specificity and safety. In a mouse tumor model (DA-3, murine breast cancer cells), we show that intratumoral injection of SurBaxS184del resulted in tumor growth retardation to the same level as CMV-Bax. This study highlights the effectiveness of using bax mutants in combination with survivin promoter for tumor-targeted suicide gene therapy in a nonviral vector.

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The permeability transition pore triggers Bax translocation to mitochondria during neuronal apoptosis

Cited by 74 publications

References 43 publications

Bioenergetic analysis of cerebellar granule neurons undergoing apoptosis by potassium/serum deprivation

Bioenergetic analysis of cerebellar granule neurons undergoing apoptosis by potassium/serum deprivation

Multistep and multitask Bax activation

Improved nonviral cancer suicide gene therapy using survivin promoter-driven mutant Bax

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