Imperial College London
Alternate

Dr Kambiz N. Alavian, PhD, SFHEA, FLS, FRSB

Faculty of Medicine, Department of Brain Sciences

Reader in Neuroscience
 
 
 
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Contact

 

+44 (0)20 7594 7006k.alavian Website

 
 
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Assistant

 

Mrs Hadeel Abdeen +44 (0)20 7594 7014

 
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Location

 

E507Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Park:2017:10.1038/cdd.2017.123,
author = {Park, H-A and Licznerski, P and Mnatsakanyan, N and Niu, Y and Sacchetti, S and Wu, J and Polster, BM and Alavian, KN and Jonas, EA},
doi = {10.1038/cdd.2017.123},
journal = {Cell Death and Differentiation},
pages = {1963--1974},
title = {Inhibition of Bcl-xL prevents pro-death actions of ΔN-Bcl-xL at the mitochondrial inner membrane during glutamate excitotoxicity.},
url = {http://dx.doi.org/10.1038/cdd.2017.123},
volume = {24},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 mit
AU  - Park,H-A
AU  - Licznerski,P
AU  - Mnatsakanyan,N
AU  - Niu,Y
AU  - Sacchetti,S
AU  - Wu,J
AU  - Polster,BM
AU  - Alavian,KN
AU  - Jonas,EA
DO  - 10.1038/cdd.2017.123
EP  - 1974
PY  - 2017///
SN  - 1350-9047
SP  - 1963
TI  - Inhibition of Bcl-xL prevents pro-death actions of ΔN-Bcl-xL at the mitochondrial inner membrane during glutamate excitotoxicity.
T2  - Cell Death and Differentiation
UR  - http://dx.doi.org/10.1038/cdd.2017.123
UR  - https://www.ncbi.nlm.nih.gov/pubmed/28777375
UR  - http://hdl.handle.net/10044/1/52137
VL  - 24
ER  -
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