Inhibition of Bcl-xL prevents pro-death actions of ΔN-Bcl-xL at the mitochondrial inner membrane during glutamate excitotoxicity.
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
ABT-737 is a pharmacological inhibitor of the anti-apoptotic activity of B-cell lymphoma-extra large (Bcl-xL) protein; it promotes apoptosis of cancer cells by occupying the BH3-binding pocket. We have shown previously that ABT-737 lowers cell metabolic efficiency by inhibiting ATP synthase activity. However, we also found that ABT-737 protects rodent brain from ischemic injury in vivo by inhibiting formation of the pro-apoptotic, cleaved form of Bcl-xL, ΔN-Bcl-xL. We now report that a high concentration of ABT-737 (1 μM), or a more selective Bcl-xL inhibitor WEHI-539 (5 μM) enhances glutamate-induced neurotoxicity while a low concentration of ABT-737 (10 nM) or WEHI-539 (10 nM) is neuroprotective. High ABT-737 markedly increased ΔN-Bcl-xL formation, aggravated glutamate-induced death and resulted in the loss of mitochondrial membrane potential and decline in ATP production. Although the usual cause of death by ABT-737 is thought to be related to activation of Bax at the outer mitochondrial membrane due to sequestration of Bcl-xL, we now find that low ABT-737 not only prevents Bax activation, but it also inhibits the decline in mitochondrial potential produced by glutamate toxicity or by direct application of ΔN-Bcl-xL to mitochondria. Loss of mitochondrial inner membrane potential is also prevented by cyclosporine A, implicating the mitochondrial permeability transition pore in death aggravated by ΔN-Bcl-xL. In keeping with this, we find that glutamate/ΔN-Bcl-xL-induced neuronal death is attenuated by depletion of the ATP synthase c-subunit. C-subunit depletion prevented depolarization of mitochondrial membranes in ΔN-Bcl-xL expressing cells and substantially prevented the morphological change in neurites associated with glutamate/ΔN-Bcl-xL insult. Our findings suggest that low ABT-737 or WEHI-539 promotes survival during glutamate toxicity by preventing the effect of ΔN-Bcl-xL on mitochondrial inner membrane depolarization, highlighting ΔN-Bcl-xL as an important therapeutic target in injured brain.
Date Issued
2017-08-04
Date Acceptance
2017-06-05
Citation
Cell Death and Differentiation, 2017, 24 (11), pp.1963-1974
ISSN
1350-9047
Publisher
Nature Publishing Group
Start Page
1963
End Page
1974
Journal / Book Title
Cell Death and Differentiation
Volume
24
Issue
11
Copyright Statement
© 2017 The Author(s). This work is licensed under a Creative Commons
Attribution-NonCommercial-ShareAlike 4.0 International
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s Creative Commons license, unless indicated
otherwise in the credit line; if the material is not included under the
Creative Commons license, users will need to obtain permission from
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license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
License. The images or other third party material in this article are
included in the article
’
s Creative Commons license, unless indicated
otherwise in the credit line; if the material is not included under the
Creative Commons license, users will need to obtain permission from
the license holder to reproduce the material. To view a copy of this
license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/28777375
PII: cdd2017123
Subjects
06 Biological Sciences
11 Medical And Health Sciences
Biochemistry & Molecular Biology
Publication Status
Published
Coverage Spatial
England