title: Metabolic and antioxidant system alterations in an astrocytoma cell line challenged with mitochondrial DNA deletion.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Biomedical Research Institute, Idaho State University, Pocatello, ID 83209, USA.
authors.forename: Alfred Orina
authors.initials: AO
authors.lastname: Isaac
authors.forename: Vikas V
authors.initials: VV
authors.lastname: Dukhande
authors.forename: James C K
authors.initials: JC
authors.lastname: Lai
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D001254:Astrocytoma / Q000378:metabolism*; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000502:physiology*; D042963:Electron Transport Complex II / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004996:Ethidium / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004272:DNA, Mitochondrial; D007521:Isocitrate Dehydrogenase; C039355:isocitrate dehydrogenase (NADP+); D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D042963:Electron Transport Complex II; C511268:SDHA protein, human; C507225:MT-ND6 protein, human; D009245:NADH Dehydrogenase; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV; D004996:Ethidium; D005978:Glutathione