Why does SOD overexpression sometimes enhance, sometimes decrease, hydrogen peroxide production? A minimalist explanation.

Abstract

Toxic effects of superoxide dismutase (SOD) overexpression are commonly attributed to increased hydrogen peroxide (H(2)O(2)) production. Still, published experiments yield contradictory evidence on whether SOD overexpression increases or decreases H(2)O(2) production. We analyzed this issue using a minimal mathematical model. The most relevant mechanisms of superoxide consumption are treated as pseudo first-order processes, and both superoxide production and the activity of enzymes other than SOD were considered constant. Even within this simple framework, SOD overexpression may increase, hold constant, or decrease H(2)O(2) production. At normal SOD levels, the outcome depends on the ratio between the rate of processes that consume superoxide without forming H(2)O(2) and the rate of processes that consume superoxide with high (>/= 1) H(2)O(2) yield. In cells or cellular compartments where this ratio is exceptionally low (< 1), a modest decrease in H(2)O(2) production upon SOD overexpression is expected. Where the ratio is higher than unity, H(2)O(2) production should increase, but at most linearly, with SOD activity. The results are consistent with the available experimental observations. According to the minimal model, only where most superoxide is eliminated through H(2)O(2)-free processes does SOD activity have the moderately large influence on H(2)O(2) production observed in some experiments.