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Inhibition of Bcl-xL prevents pro-death actions of ¿N-Bcl-xL at the mitochondrial inner membrane during glutamate excitotoxicity.

Authors: Park, Han-A  Licznerski, Pawel  Mnatsakanyan, Nelli  Niu, Yulong  Sacchetti, Silvio  Wu, Jing  Polster, Brian M  Alavian, Kambiz N  Jonas, Elizabeth A 
Citation: Park HA, etal., Cell Death Differ. 2017 Nov;24(11):1963-1974. doi: 10.1038/cdd.2017.123. Epub 2017 Aug 4.
Pubmed: (View Article at PubMed) PMID:28777375
DOI: Full-text: DOI:10.1038/cdd.2017.123

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, ¿N-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 ¿N-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 ¿N-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 ¿N-Bcl-xL. In keeping with this, we find that glutamate/¿N-Bcl-xL-induced neuronal death is attenuated by depletion of the ATP synthase c-subunit. C-subunit depletion prevented depolarization of mitochondrial membranes in ¿N-Bcl-xL expressing cells and substantially prevented the morphological change in neurites associated with glutamate/¿N-Bcl-xL insult. Our findings suggest that low ABT-737 or WEHI-539 promotes survival during glutamate toxicity by preventing the effect of ¿N-Bcl-xL on mitochondrial inner membrane depolarization, highlighting ¿N-Bcl-xL as an important therapeutic target in injured brain.

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CRRD Object Information
CRRD ID: 13800748
Created: 2018-10-17
Species: All species
Last Modified: 2018-10-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.