Accumulation of manganese superoxide dismutase under metal-depleted conditions: proposed role for zinc ions in cellular redox balance

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Abstract
A diet low in copper results in increased levels of MnSOD (manganese superoxide dismutase), a critical antioxidative enzyme conferring protection against oxidative stress, in rat liver mitochondria. The mechanism for this was investigated using cultured HepG2 cells, a human hepatocellular carcinoma-derived line. MnSOD activity increased 5–7-fold during incubation in a medium supplemented with metal-depleted fetal bovine serum, with a corresponding elevation of its mRNA levels. Metal depletion also decreased CuZnSOD and glutathione peroxidase levels to approx. 70–80% of baseline. When zinc ions were added to the medium at micromolar levels, MnSOD accumulation was suppressed; however, copper ions had essentially no effect on MnSOD expression. Since the intracellular redox status was shifted to a more oxidized state by metal depletion, we examined the DNA-binding activity of NF-κB (nuclear factor-κB), an oxidative stress-sensitive transactivating factor that plays a primary role in MnSOD induction. A gel shift assay indicated that the DNA-binding activity of NF-κB was increased in cells maintained in metal-depleted culture, suggesting the involvement of the transactivating function of NF-κB in this induction. This was further supported by the observation that curcumin suppressed both the DNA-binding activity of NF-κB and the induction of MnSOD mRNA in cells cultivated under metal-depleted conditions. These results suggest that the level of zinc, rather than copper, is a critical regulatory factor in MnSOD expression. It is possible that a deficiency of zinc in the low-copper diet may be primarily involved in MnSOD induction.
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