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

Toxic effects of superoxide dismutase (SOD) overexpression are commonly attributed to increased hydrogen peroxide (H2O2) production. Still, published experiments yield contradictory evidence on whether SOD overexpression increases or decreases H2O2 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 H2O2 production. At normal SOD levels, the outcome depends on the ratio between the rate of processes that consume superoxide without forming H2O2 and the rate of processes that consume superoxide with high (greater than or equal to 1) H2O2 yield. In cells or cellular compartments where this ratio is exceptionally low (< 1), a modest decrease in H2O2 production upon SOD overexpression is expected. Where the ratio is higher than unity, H2O2 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 H2O2-free processes does SOD activity have the moderately large influence on H2O2 production observed in some experiments. (C) 2002 Elsevier Science Inc.