Vitamin E Prevents ?N-Bcl-xL-associate Mitochondrial Dysfunction in Primary Hippocampal Neurons (P14-024-19). Academic Article uri icon

abstract

  • Objectives: B-cell lymphoma-extra large (Bcl-xL) is a pro-survival protein localized to mitochondria. Bcl-xL is reported to support brain function by enhancing neuronal energy metabolism, synapse formation, and neurite outgrowth. However, under exposure to excitotoxic stimulation and subsequent oxidative stress, Bcl-xL undergoes caspase dependent cleavage to ?N-Bcl-xL. Accumulation of ?N-Bcl-xL is associated with neuronal death; thus, approaches that prevent ?N-Bcl-xL accumulation protect neurons from excitotoxic insult. In this study, we hypothesize that ?N-Bcl-xL formation is regulated by redox status in mitochondria. We thus tested if production of ?N-Bcl-xL can be inhibited by the fat-soluble antioxidant ?-tocotrienol (TCT) given its ability to scavenge free radicals produced in the mitochondrial membrane. Methods: Primary hippocampal neurons were treated with ?-TCT, glutamate, or a combination of both, and mitochondrial oxidative stress, mitochondrial potential, caspase activity, and ?N-Bcl-xL protein levels were quantified. Results: Glutamate caused abnormalities in mitochondrial function leading to neuronal death. The antioxidant ?-TCT protected neurons from glutamate-induced mitochondrial dysfunction and cytotoxicity. ?-TCT treatment protected against cleavage of full length anti-apoptotic Bcl-xL to form pro-death ?N-Bcl-xL. ?-TCT significantly attenuated glutamate-induced reactive oxygen species (ROS) formation, caspase 3 activation and ?N-Bcl-xL formation at mitochondria. Conclusions: Our data suggests that oxidative stress production during excitotoxicity is responsible for the formation of ?N-Bcl-xL. Thus, application of a lipophilic antioxidant such as vitamin E is neuroprotective by improving mitochondrial redox status and preventing production of neurotoxic ?N-Bcl-xL. Funding Sources: -NINDS, RO1-University of Alabama, RGC internal grant.

publication date

  • June 2019