Metabolic and Antioxidant System Alterations in an Astrocytoma Cell Line Challenged with Mitochondrial DNA Deletion |
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Authors: | Alfred Orina Isaac Vikas V Dukhande James C K Lai |
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Institution: | (1) Department of Pharmaceutical Sciences, College of Pharmacy and Biomedical Research Institute, Idaho State University, Pocatello, ID 83209, USA;(2) Mountain States Tumor and Medical Research Institute, Boise, ID 83712, USA |
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Abstract: | Oxidative stress can induce mitochondrial dysfunction, mitochondrial DNA (mtDNA) depletion, and neurodegeneration, although
the underlying mechanisms are poorly understood. The major mitochondrial antioxidant system that protects cells consists of
manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx) and glutathione (GSH). To investigate the putative adaptive
changes in antioxidant enzyme protein expression and targeting to mitochondria as mtDNA depletion occurs, we progressively
depleted U87 astrocytoma cells of mtDNA by chronic treatment with ethidium bromide (EB, 50 ng/ml). Cellular MnSOD protein
expression was markedly increased in a time-related manner while that of GPx showed time-related decreases. The mtDNA depletion
also altered targeting or subcellular distribution of GPx, suggesting the importance of intact mtDNA in mitochondrial genome-nuclear
genome signaling/communication. Cellular NADP+-ICDH activity also showed marked, time-related increases while their GSH content decreased. Thus, our findings suggest that
interventions to elevate MnSOD, GPx, NADP+-ICDH, and GSH levels may protect brain cells from oxidative stress. |
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Keywords: | Astrocytoma mtDNA Neurodegeneration Astrocytes Oxidative stress Mitochondrial genome-nuclear genome signaling |
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