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Open AccessArticle

Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons

1
Department of Human Nutrition and Hospitality Management, College of Human Environmental Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
2
Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT 06511, USA
3
Department of Biological Sciences, College of Arts and Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(1), 220; https://doi.org/10.3390/ijms21010220
Received: 17 May 2019 / Revised: 24 December 2019 / Accepted: 25 December 2019 / Published: 28 December 2019
(This article belongs to the Special Issue Advances in Bcl-xL Research)
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. View Full-Text
Keywords: Bcl-xL; ∆N-Bcl-xL; antioxidant; mitochondria; tocotrienol Bcl-xL; ∆N-Bcl-xL; antioxidant; mitochondria; tocotrienol
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MDPI and ACS Style

Park, H.-A; Mnatsakanyan, N.; Broman, K.; Davis, A.U.; May, J.; Licznerski, P.; Crowe-White, K.M.; Lackey, K.H.; Jonas, E.A. Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons. Int. J. Mol. Sci. 2020, 21, 220. https://doi.org/10.3390/ijms21010220

AMA Style

Park H-A, Mnatsakanyan N, Broman K, Davis AU, May J, Licznerski P, Crowe-White KM, Lackey KH, Jonas EA. Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons. International Journal of Molecular Sciences. 2020; 21(1):220. https://doi.org/10.3390/ijms21010220

Chicago/Turabian Style

Park, Han-A; Mnatsakanyan, Nelli; Broman, Katheryn; Davis, Abigail U.; May, Jordan; Licznerski, Pawel; Crowe-White, Kristi M.; Lackey, Kimberly H.; Jonas, Elizabeth A. 2020. "Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons" Int. J. Mol. Sci. 21, no. 1: 220. https://doi.org/10.3390/ijms21010220

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