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.

Mitochondrial Function and Nuclear Factor-κB–Mediated Signaling in Radiation-Induced Bystander Effects

“…1B-D). There is evidence that, in U o cells with a complete shutdown of the electron transport chain, the decreased level of reactive oxygen species resulted in a down-regulation of the manganese superoxide dismutase, glutathione, and glutathione peroxidase, an important intracellular antioxidant pool (31). As such, compared with wild-type cells, U o cells are more susceptible to oxidative stress and expressed in a higher bystander mutagenesis as shown in the present studies.…”

Suppression of methylmercury-induced IL-6 and MCP-1 expressions by N-acetylcysteine in U-87MG human astrocytoma cells

“…Oxidative stress generation has been known to be involved in MeHg-induced cytotoxicity at low dose exposure (0.05 mg/kg/day) in neuronal mice [21]. It is well known that O 2 − is converted to H 2 O 2 and O 2 through the enzyme activity of superoxide dismutase (SOD) in astrocytoma cells under the oxidative stress [23]. Thus, our findings suggest that the increased level of intracellular H 2 O 2 but not O 2 may involve the dismutation from O 2 − to H 2 O 2 and O 2 through SOD under lowlevel exposure of MeHg.…”

Neuroprotection against neuroblastoma cell death induced by depletion of mitochondrial glutathione

“…In addition, we have also shown that depletion of mitochondrial DNA results in decrease in GSH and alterations of antioxidant enzymes [40]. Moreover, GSH depletion and resultant oxidative stress and apoptosis has been studied [41–43].…”