Cargando…
Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons
B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic member of the Bcl2 family of proteins, which supports neurite outgrowth and neurotransmission by improving mitochondrial function. During excitotoxic stimulation, however, Bcl-xL undergoes post-translational cleavage to ∆N-Bcl-xL, and accumul...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982044/ https://www.ncbi.nlm.nih.gov/pubmed/31905614 http://dx.doi.org/10.3390/ijms21010220 |
_version_ | 1783491224432279552 |
---|---|
author | Park, Han-A Mnatsakanyan, Nelli Broman, Katheryn Davis, Abigail U. May, Jordan Licznerski, Pawel Crowe-White, Kristi M. Lackey, Kimberly H. Jonas, Elizabeth A. |
author_facet | Park, Han-A Mnatsakanyan, Nelli Broman, Katheryn Davis, Abigail U. May, Jordan Licznerski, Pawel Crowe-White, Kristi M. Lackey, Kimberly H. Jonas, Elizabeth A. |
author_sort | Park, Han-A |
collection | PubMed |
description | B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic member of the Bcl2 family of proteins, which supports neurite outgrowth and neurotransmission by improving mitochondrial function. During excitotoxic stimulation, however, Bcl-xL undergoes post-translational cleavage to ∆N-Bcl-xL, and accumulation of ∆N-Bcl-xL causes mitochondrial dysfunction and neuronal death. In this study, we hypothesized that the generation of reactive oxygen species (ROS) during excitotoxicity leads to formation of ∆N-Bcl-xL. We further proposed that the application of an antioxidant with neuroprotective properties such as α-tocotrienol (TCT) will prevent ∆N-Bcl-xL-induced mitochondrial dysfunction via its antioxidant properties. Primary hippocampal neurons were treated with α-TCT, glutamate, or a combination of both. Glutamate challenge significantly increased cytosolic and mitochondrial ROS and ∆N-Bcl-xL levels. ∆N-Bcl-xL accumulation was accompanied by intracellular ATP depletion, loss of mitochondrial membrane potential, and cell death. α-TCT prevented loss of mitochondrial membrane potential in hippocampal neurons overexpressing ∆N-Bcl-xL, suggesting that ∆N-Bcl-xL caused the loss of mitochondrial function under excitotoxic conditions. Our data suggest that production of ROS is an important cause of ∆N-Bcl-xL formation and that preventing ROS production may be an effective strategy to prevent ∆N-Bcl-xL-mediated mitochondrial dysfunction and thus promote neuronal survival. |
format | Online Article Text |
id | pubmed-6982044 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69820442020-02-07 Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons Park, Han-A Mnatsakanyan, Nelli Broman, Katheryn Davis, Abigail U. May, Jordan Licznerski, Pawel Crowe-White, Kristi M. Lackey, Kimberly H. Jonas, Elizabeth A. Int J Mol Sci Article B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic member of the Bcl2 family of proteins, which supports neurite outgrowth and neurotransmission by improving mitochondrial function. During excitotoxic stimulation, however, Bcl-xL undergoes post-translational cleavage to ∆N-Bcl-xL, and accumulation of ∆N-Bcl-xL causes mitochondrial dysfunction and neuronal death. In this study, we hypothesized that the generation of reactive oxygen species (ROS) during excitotoxicity leads to formation of ∆N-Bcl-xL. We further proposed that the application of an antioxidant with neuroprotective properties such as α-tocotrienol (TCT) will prevent ∆N-Bcl-xL-induced mitochondrial dysfunction via its antioxidant properties. Primary hippocampal neurons were treated with α-TCT, glutamate, or a combination of both. Glutamate challenge significantly increased cytosolic and mitochondrial ROS and ∆N-Bcl-xL levels. ∆N-Bcl-xL accumulation was accompanied by intracellular ATP depletion, loss of mitochondrial membrane potential, and cell death. α-TCT prevented loss of mitochondrial membrane potential in hippocampal neurons overexpressing ∆N-Bcl-xL, suggesting that ∆N-Bcl-xL caused the loss of mitochondrial function under excitotoxic conditions. Our data suggest that production of ROS is an important cause of ∆N-Bcl-xL formation and that preventing ROS production may be an effective strategy to prevent ∆N-Bcl-xL-mediated mitochondrial dysfunction and thus promote neuronal survival. MDPI 2019-12-28 /pmc/articles/PMC6982044/ /pubmed/31905614 http://dx.doi.org/10.3390/ijms21010220 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Park, Han-A Mnatsakanyan, Nelli Broman, Katheryn Davis, Abigail U. May, Jordan Licznerski, Pawel Crowe-White, Kristi M. Lackey, Kimberly H. Jonas, Elizabeth A. Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons |
title | Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons |
title_full | Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons |
title_fullStr | Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons |
title_full_unstemmed | Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons |
title_short | Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons |
title_sort | alpha-tocotrienol prevents oxidative stress-mediated post-translational cleavage of bcl-xl in primary hippocampal neurons |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982044/ https://www.ncbi.nlm.nih.gov/pubmed/31905614 http://dx.doi.org/10.3390/ijms21010220 |
work_keys_str_mv | AT parkhana alphatocotrienolpreventsoxidativestressmediatedposttranslationalcleavageofbclxlinprimaryhippocampalneurons AT mnatsakanyannelli alphatocotrienolpreventsoxidativestressmediatedposttranslationalcleavageofbclxlinprimaryhippocampalneurons AT bromankatheryn alphatocotrienolpreventsoxidativestressmediatedposttranslationalcleavageofbclxlinprimaryhippocampalneurons AT davisabigailu alphatocotrienolpreventsoxidativestressmediatedposttranslationalcleavageofbclxlinprimaryhippocampalneurons AT mayjordan alphatocotrienolpreventsoxidativestressmediatedposttranslationalcleavageofbclxlinprimaryhippocampalneurons AT licznerskipawel alphatocotrienolpreventsoxidativestressmediatedposttranslationalcleavageofbclxlinprimaryhippocampalneurons AT crowewhitekristim alphatocotrienolpreventsoxidativestressmediatedposttranslationalcleavageofbclxlinprimaryhippocampalneurons AT lackeykimberlyh alphatocotrienolpreventsoxidativestressmediatedposttranslationalcleavageofbclxlinprimaryhippocampalneurons AT jonaselizabetha alphatocotrienolpreventsoxidativestressmediatedposttranslationalcleavageofbclxlinprimaryhippocampalneurons |